Inhibiting ubiquitin specific peptidase 30

ABSTRACT

The present disclosure relates to chemical entities useful as inhibitors of Ubiquitin Specific Peptidase 30 (USP30), pharmaceutical compositions comprising the chemical entities, and methods of using the chemical entities. The chemical entities as disclosed herein can be useful in the treatment of a disease, disorder, or condition involving mitochondrial dysfunction, including neurodegenerative diseases, motor neuron diseases, metabolic disorders, and cancers, among other ailments.

The present patent application is a divisional application of U.S.application Ser. No. 16/753,439, filed on Apr. 3, 2020, which is a U.S.National Stage Application of PCT/US18/54520, filed Oct. 5, 2018, whichclaims the benefit of U.S. Provisional Patent Application No.62/569,177, filed Oct. 6, 2017, which is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present disclosure is directed to novel chemical entities, methodsfor their preparation, synthesis and manufacture, which can act asinhibitors of Ubiquitin Specific Peptidase 30 (USP30), a member of thedeubiquitinating (DUB) enzyme family. The present disclosure alsodescribes the use of these USP30 inhibitors in the treatment of diseasesor disorders associated with USP30 enzymes, such as the treatment ofmitochondrial dysfunction diseases or disorders, neurodegenerativediseases, and in the treatment of cancer. Specifically, the disclosureis concerned with chemical entities and compositions inhibiting USP30,methods of treating diseases or disorders associated with USP30, andmethods of synthesis of these compounds.

BACKGROUND

The ubiquitination system is a highly-regulated process which affects awide variety of cellular activities and physiological processes.Dysregulation of this system is commonly associated with several humandiseases, including cancer, neurodegenerative disorders, muscledystrophies, and cardiomyophaties, amongst others (Popovic, et al.,Nature Medicine 2014, 20, 1242-1253). Ubiquitination is a reversibleprocess, facilitated by a group of proteins known as deubiquitinatingenzymes (DUBs), which deconjugate ubiquitin (Ub) from the substrate.DUBs are encoded by approximately 100 human genes and are divided intosix families, with the largest family being the ubiquitin-specificproteases (USPs) with more than 50 members.

Ubiquitin regulates mitochondrial dynamics and biogenesis, affecting theabundance and function of these organelles. Many age-related diseases,particularly neurodegenerative disorders, have been linked tomitochondrial dysfunction and impairment of the ubiquitination system(Ross, et al., Int J Mol Sci. 2015, 16(8), 19458-19476).

Parkinson's disease (PD) is a neurodegenerative disorder that affectsmore than 10 million people worldwide, including 60,000 new diagnoses ayear in the US alone (Parkinson's Disease Foundation, www.pdf.org). PDis characterized by the loss of dopaminergic neurons in the substantianigra. Although the exact mechanism of neuronal loss is not yet fullyelucidated, an increasing body of evidence links mitochondrialdysfunction with dopaminergic neuron vulnerability.

Mitophagy, the clearance of dysfunctional mitochondria throughautophagy, appears to be specifically important in certain geneticallydefined subsets of Parkinson's patients. Loss-of-function mutations inPRKN (gene encoding the Parkin protein) present as a form of autosomalrecessive juvenile Parkinsonism (AR-JP) (Shimura, et al., Nat Genet.2000, 25(3), 302-305; Sriram, et al., Hum Mol Genet. 2005, 14(17),2571-2586; Ekholm-Reed, et al., Mol Cell Biol. 2013, 33(18), 3627-3643).In the late 1990's genetic analysis of Japanese families revealed thatmutations in PARK2 (nPRKN) were responsible for AR-JP (Matsumine, etal., Am J Hum Genet. 1997, 60(3), 588-596). Subsequent investigation ofdifferent ethnic populations independently replicated the associationbetween PRKN mutations and early-onset PD. Later genetic work identifiedmutations in PINK1 which result in early-onset recessive PD (Valente, etal., Science. 2004, 304(5674), 1158-1160; Valente, et al., Ann Neurol.2004, 56(3), 336-341).

Parkin (E3 ubiquitin ligase) and PINK1 (kinase) are key regulators ofmitophagy. In healthy mitochondria, PINK1 localization to themitochondrial outer membrane (MOM) and exposure to the cytosol islimited by rapid import to the mitochondrial inner membrane (MIM). Oncelocalized to the MIM, PINK1 is processed by several proteases, such aspresenilin associated rhomboid-like protease (PARL), to yield atruncated version of PINK1 which is subsequently degraded by theproteasome (Meissner et al., Autophagy. 2015, 11(9), 1484-1498). Uponmitochondrial depolarization or dysfunction, PINK1 accumulates in themitochondrial outer membrane (MOM), recruiting and activating Parkin viaPINK1-dependent phosphorylation of both ubiquitin and Parkin.Consequently, activated Parkin ubiquitinates MOM proteins like TOMM20 totrigger mitophagy (Pickrell et al., Neuron. 2015, 85(2), 257-273).

USP30 is embedded in the MOM with its catalytic DUB domain orientedtowards the cytosol and has been shown to antagonize Parkin-mediatedubiquitination of common substrates, consequently opposingParkin-mediated mitophagy. Genetic silencing of USP30 results inincreased ubiquitination of several Parkin substrates followed byincreased mitophagy. In model organisms, USP30 depletion is able torescue mitophagy defects caused by pathogenic Parkin mutations, as wellas restore mitochondria morphology and function, and dopamine levels.(Nakamura, et al., Mol Biol Cell. 2008, 19(5), 1903-1911; Bingol, etal., Nature 2014, 510(7505):370-5). Therefore, inhibition of USP30 couldpresent a novel treatment paradigm for PD, by promoting mitochondrialturnover.

USP30 inhibition could also benefit patients with other indicationswhich involve mitochondria function, including but not limited to,neurodegenerative diseases, motor neuron diseases, metabolic disorders,cardio-vascular diseases, psychiatric diseases, osteoarthritis, andcancer. For example, mitochondria play a central role in apoptotic celldeath. The key event in this process is BAX/BAK-dependent mitochondrialouter-membrane permeabilization. USP30 regulates BAX/BAK-dependentapoptosis, and its depletion sensitizes cancer cells to ABT-737, a BCL-2inhibitor/BH3-mimetic (Liang, et al., EMBO reports 2015, 16, 618-627).These studies suggest a utility for a USP30 inhibitor in anti-cancertherapy.

There remains a need for USP30 inhibitor compounds. Such compounds wouldbe useful, for example, in the development of new therapies forParkinson's disease.

SUMMARY

The present disclosure provides compounds of Formula (Ia):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, and (C₃-C₆) heterocycloalkylgroups;

n is 0, 1, or 2;

wherein, if n is 2, the R groups can combine to form a fused ring systemwith R₁;

R₁ is a 4-membered cyclic or heterocyclic group;

R₂ is chosen from C(X)_(n), S(O)₂, N(X), heteroatom linkers, N(X)S(O)₂,N(X)S(O)₂N(X), carbonylalkyl groups, and carbonylheteroalkyl groups,wherein the alkyl portion of carbonylalkyl and carbonylheteroalkylgroups can optionally cyclize with R, R₁, or R₃;

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R, R₁, or R₃ or with another X group when multiple X groups arepresent;

R₃ is chosen from hydrogen, halogens, alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, heteroalkoxy groups, haloalkoxy groups,carbonylalkyl groups, carbonylheteroalkyl groups, cyclic groups,heterocyclic groups, aryl groups, and heteroaryl groups, wherein anyrings are optionally substituted with 1 or 2 R groups;

R₄ is independently chosen from alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, cycloalkoxy groups, heteroalkoxygroups, haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkylgroups, cyclic groups, heterocyclic groups, aryl groups and heteroarylgroups, wherein any rings are optionally substituted with 1 or 2 Ygroups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups; and

m is 0, 1, or 2.

The present disclosure provides compounds of Formula (Ib):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, and (C₃-C₆) heterocycloalkylgroups;

n is 0, 1, or 2; wherein, if n is 2, the R groups can combine to form afused ring system with R₁;

R₁ is chosen from 3-6 membered cyclic or heterocyclic groups;

R₂ is chosen from carbonylheteroalkyl groups, wherein the alkyl portionof the carbonylheteroalkyl group can optionally cyclize with R, R₁, orR₃;

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R, R₁, or R₃ or with another X group when multiple X groups arepresent;

R₃ is chosen from hydrogen, halogens, alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, heteroalkoxy groups, haloalkoxy groups,carbonylalkyl groups, carbonylheteroalkyl groups, cyclic groups,heterocyclic groups, aryl groups, and heteroaryl groups, wherein anyrings are optionally substituted with 1 or 2 R groups;

R₄ is independently chosen from alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, cycloalkoxy groups, heteroalkoxygroups, haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkylgroups, cyclic groups, heterocyclic groups, aryl groups and heteroarylgroups, wherein any rings are optionally substituted with 1 or 2 Ygroups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups; and

m is 0, 1, or 2.

The present disclosure provides compounds of Formula (Ic):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, and (C₃-C₆) heterocycloalkylgroups;

n is 0, 1, or 2; wherein, if n is 2, the R groups can combine to form afused ring system with R₁;

R₁ is a 4-membered cyclic or heterocyclic group;

R₂ is a carbonylheteroalkyl group, wherein the alkyl portion of thecarbonylheteroalkyl group can optionally cyclize with R, R₁, or R₃;

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R, R₁, or R₃ or with another X group when multiple X groups arepresent;

R₃ is chosen from hydrogen, halogens, alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, heteroalkoxy groups, haloalkoxy groups,carbonylalkyl groups, carbonylheteroalkyl groups, cyclic groups,heterocyclic groups, aryl groups, and heteroaryl groups, wherein anyrings are optionally substituted with 1 or 2 R groups;

R₄ is independently chosen from alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, cycloalkoxy groups, heteroalkoxygroups, haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkylgroups, cyclic groups, heterocyclic groups, aryl groups and heteroarylgroups, wherein any rings are optionally substituted with 1 or 2 Ygroups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups; and

m is 0, 1, or 2.

The present disclosure provides compounds of Formula (II):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

A is N or CR_(b);

R_(a) is selected from the group consisting of hydrogen and (C₁-C₆)alkyl groups;

R_(b) is selected from the group consisting of: hydrogen, halogen, OH,(C₁-C₆) alkyl groups optionally substituted with one or more R₅ and(C₁-C₆) alkoxy groups optionally substituted with one or more R₅; or

R_(b) and X together form a (C₃-C₆) spirocyclic cycloalkyl or (C₃-C₆)spirocyclic heterocycloalkyl;

each of R_(c), R_(d), R_(e) and R_(f) is independently selected from thegroup consisting of: hydrogen, halogen, —OR₅ and (C₁-C₆) alkyl groupsoptionally substituted with one or more R₅;

R₂ is selected from the group consisting of: C(O)N(X), N(X)C(O);

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R_(b), or R₃;

R₁ is selected from the group consisting of: (C₁-C₆) alkyl (e.g., alinker to R₄, or when X forms a cycloalkyl together with R₃), (C₃-C₆)cycloalkyl, (C₁-C₆) heteroalkyl (e.g., when X forms a heterocyclyltogether with R₃), aryl having 1 to 3 aromatic rings (including arylgroups optionally substituted with 1 or 2 R groups) and heteroarylhaving 1 to 3 aromatic rings (including heteroaryl groups optionallysubstituted with 1 or 2 R groups);

R₄ (present when m is 1 or 2) is independently chosen from alkyl groups,cycloalkyl groups, heteroalkyl groups, haloalkyl groups, alkoxy groups,cycloalkoxy groups, heteroalkoxy groups, haloalkoxy groups, carboxyalkylgroups, heterocarboxyalkyl groups, cyclic groups, heterocyclic groups,aryl groups and heteroaryl groups, wherein any rings are optionallysubstituted with 1 or 2 Y groups;

R₅ is selected from the group consisting of: hydrogen, halogen, OH,(C₁-C₃) alkyl groups, and (C₁-C₃) alkoxy groups;

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, (C₃-C₆) heterocycloalkylgroups; (C₃-C₆)cycloalkyloxy groups and (C₁-C₆) alkoxyalkyl groups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, (C₄-C₈)heteroaryl groups, and (C₄-C₈) heteroaryl groups substituted with C₁-C₃alkyl; and

m is 0, 1, or 2.

The present disclosure provides compounds of Formula (III):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R_(a) is selected from the group consisting of hydrogen and (C₁-C₆)alkyl groups;

R_(b) is selected from the group consisting of: hydrogen, halogen, OH,(C₁-C₆) alkyl groups optionally substituted with one or more R₅ and(C₁-C₆) alkoxy groups optionally substituted with one or more R₅; or

R_(b) and X together form a (C₃-C₆) spirocyclic cycloalkyl or (C₃-C₆)spirocyclic heterocycloalkyl;

each of R_(c), R_(d), R_(e) and R_(f) is independently selected from thegroup consisting of: hydrogen, halogen, —OR₅ and (C₁-C₆) alkyl groupsoptionally substituted with one or more R₅;

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R_(b), or R₃;

R₃ is selected from the group consisting of: (C₁-C₃) alkyl, (C₁-C₃)heteroalkyl, and 5-10 membered cyclic, heterocyclic, aryl, andheteroaryl groups, wherein any of the rings can be optionallysubstituted with 1 or 2 R groups;

R₄ (present when m is 1 or 2) is independently chosen from alkyl groups,cycloalkyl groups, heteroalkyl groups, haloalkyl groups, alkoxy groups,cycloalkoxy groups, heteroalkoxy groups, haloalkoxy groups, carboxyalkylgroups, heterocarboxyalkyl groups, cyclic groups, heterocyclic groups,aryl groups and heteroaryl groups, wherein any rings are optionallysubstituted with 1 or 2 Y groups;

R₅ is selected from the group consisting of: hydrogen, halogen, OH,(C₁-C₃) alkyl groups, and (C₁-C₃) alkoxy groups;

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, (C₃-C₆) heterocycloalkylgroups; (C₃-C₆)cycloalkyloxy groups and (C₁-C₆) alkoxyalkyl groups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups, and (C₄-C₈) heteroaryl groups substitutedwith C₁-C₃ alkyl; and

m is 0, 1, or 2.

The present disclosure also provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, and (C₃-C₆) heterocycloalkylgroups;

n is 0, 1, or 2; wherein, if n is 2, the R groups can combine to form afused ring system with R₁;

R₁ is chosen from 3-6 membered cyclic or heterocyclic groups;

R₂ is chosen from C(X)_(n), S(O)₂, N(X), heteroatom linkers, N(X)S(O)₂,N(X)S(O)₂N(X), carbonylalkyl groups, and carbonylheteroalkyl groups,wherein the alkyl portion of carbonylalkyl and carbonylheteroalkylgroups can optionally cyclize with R, R₁, or R₃: X is independentlychosen from hydrogen, alkyl groups, and heteroalkyl groups, wherein thealkyl and heteroalkyl groups can optionally cyclize with R, R₁, or R₃ orwith another X group when multiple X groups are present;

R₃ is chosen from hydrogen, halogens, alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, heteroalkoxy groups, haloalkoxy groups,carbonylalkyl groups, carbonylheteroalkyl groups, cyclic groups,heterocyclic groups, aryl groups, and heteroaryl groups, wherein anyrings are optionally substituted with 1 or 2 R groups;

R4 is independently chosen from alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, cycloalkoxy groups, heteroalkoxygroups, haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkylgroups, cyclic groups, heterocyclic groups, aryl groups and heteroarylgroups, wherein any rings are optionally substituted with 1 or 2 Ygroups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups; and

m is 0, 1, or 2.

Another aspect of the present disclosure relates to a method of treatinga disease or disorder associated with inhibition of Ubiquitin SpecificPeptidase 30 (USP30). The method comprises administering to a patient inneed of a treatment for diseases or disorders associated with inhibitionof USP30 an effective amount of at least one chemical entity chosen fromcompounds of Formula (I), and pharmaceutically acceptable salts,solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure is directed to a method of inhibitingUSP30. The method involves administering to a patient in need thereof aneffective amount of at least one chemical entity chosen from compoundsof Formula (I), and pharmaceutically acceptable salts, hydrates,solvates, prodrugs, stereoisomers, and tautomers thereof.

Another aspect of the disclosure relates to a method of treatingneurodegenerative diseases. The method comprises administering to apatient in need thereof an effective amount of at least one chemicalentity chosen from compounds of Formula (I), and pharmaceuticallyacceptable salts, solvates, prodrugs, stereoisomers, and tautomersthereof.

Preferably the compounds of the disclosure are for use in a method oftreating Parkinson's disease, wherein the method comprises administeringto a patient in need thereof an effective amount of at least onechemical entity of the disclosure or a pharmaceutically acceptable salt,solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising at least one chemical entity chosen fromcompounds of Formula (I), and pharmaceutically acceptable salts,solvates, prodrugs, stereoisomers, and tautomers thereof, and apharmaceutically acceptable carrier. The pharmaceutical acceptablecarrier may further include an excipient, diluent, or surfactant.

Another aspect of the present disclosure relates to at least onechemical entity chosen from compounds of Formula (I), andpharmaceutically acceptable salts, solvates, prodrugs, stereoisomers,and tautomers thereof, for use in the manufacture of a medicament fortreating a disease associated with inhibiting USP30.

Another aspect of the present disclosure relates to the use of at leastone chemical entity chosen from compounds of Formula (I), andpharmaceutically acceptable salts, solvates, prodrugs, stereoisomers,and tautomers thereof, in the treatment of a disease associated withinhibiting USP30.

As summarized above, and as set forth in detail below, the presentdisclosure relates to chemical entities and compositions that arecapable of inhibiting the activity of USP30. The disclosure also relatesto methods of treating, preventing or ameliorating a disease or disorderin which USP30 plays a role by administering to a patient in needthereof a therapeutically effective amount of at least one chemicalentity chosen from compounds of Formula (I), and pharmaceuticallyacceptable salts, solvates, prodrugs, stereoisomers, and tautomersthereof. The methods of the present disclosure can be used in thetreatment of a variety of USP30 dependent diseases and disorders byinhibiting the activity of USP30. Inhibition of USP30 as disclosedherein provides a novel approach to the treatment, prevention, oramelioration of diseases including, but not limited to, cancer.

DETAILED DESCRIPTION

The present disclosure describes compounds that inhibit USP30. Compoundsthat inhibit USP30 are useful in the development of novel therapies forthe treatment of diseases or disorders associated with USP30 enzymes,such as the treatment of mitochondrial dysfunction diseases ordisorders, neurodegenerative diseases, and in the treatment of cancer.Specifically, the present disclosure is concerned with chemical entitiesand compositions inhibiting USP30, methods of treating diseases ordisorders associated with USP30, and methods of synthesis of thesecompounds. In some embodiments the compounds of the invention are USP30inhibitors having an IC₅₀ value of <10 μM and >0.001 μM when tested inthe Biochemical Assay of Example A herein. Preferably, the compounds ofthe invention are USP30 inhibitors having an IC₅₀ value of <1 μMand >0.001 μM when tested in the Biochemical Assay of Example A herein.

In a first aspect of the disclosure, the chemical entities chosen fromcompounds of Formula (I):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, are described wherein R, R₁, R₂,R₃, R₄, n, and m are as described herein above. In further aspects ofthe disclosure, compounds of Formula (Ia), (Ib), and (Ic) andpharmaceutically acceptable salts, solvates, prodrugs, stereoisomers,and tautomers thereof as described herein above are provided.

In a further aspect of the disclosure, compounds of Formula (II):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof are provided, wherein A, R_(a),R_(b), R_(c), R_(d), R_(e), R_(f), R, R₂, R₃, R₄, R₅, X, Y, and m are asdescribed herein above.

In a further aspect of the disclosure, compounds of Formula (III):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof are provided, wherein R_(a), R_(b),R_(c), R_(d), R_(e), R_(f), R, R₃, R₄, R₅, X, Y, and m are as describedherein above.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl),—N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl,—S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆) alkyl, and S(O)N((C₁-C₆) alkyl)₂.The substituents can themselves be optionally substituted. “Optionallysubstituted” as used herein also refers to substituted or unsubstitutedwhose meaning is described below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to, —H,-halogen, —O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, —O—(C₂-C₆) alkenyl,—O—(C₂-C₆) alkynyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂,—OC(O)(C₁-C₆) alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂,NH((C₁-C₆) alkyl), N((C₁-C₆) alkyl)₂, —S(O)₂—(C₁-C₆) alkyl,—S(O)NH(C₁-C₆) alkyl, and —S(O)N((C₁-C₆) alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, andthe like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, O, and S, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, O, and S. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl,furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl,benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl,1,5-naphthyridinyl, furo[3,2-b]pyridine,[1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl,imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole,1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,thieno[2,3-b]pyrrolyl, thieno[2,3-d]thiazole,1a,2,3,7b-tetrahydro-1H-cyclopropa[c][1,8]naphthyridine, 3H-indolyl, andderivatives thereof. Furthermore the terms “heteroaryl” and “heteroar-”,as used herein, also include groups in which a heteroaromatic ring isfused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherethe radical or point of attachment is on the heteroaromatic ring.Nonlimiting examples include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,isoindolyl and dihydrobenzoxanyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,e.g., —O(alkyl). Examples of alkoxy groups include without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

The terms “alkylene” or “alkylenyl” refer to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As herein defined,alkylene may also be a C₀-C₆ alkylene. An alkylene may further be aC₀-C₄ alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

The term “carbonylalkyl” means an alkyl group as defined above, wherethe alkyl group is substituted with one or more C(O) groups.

The term “carbonylheteroalkyl” is similar to the carbonylalkyl group asdefined above, in that an alkyl group containing heteroatoms such as N,S, O (“heteroalkyl”), is substituted with one or more C(O) groups.Non-limiting examples of carbonylheteroalkyl groups include amide,reverse amide, and alkylamide-type groups such as NXC(O), C(X)₂NXC(O),C(O)NX, urea-type groups such as NXC(O)NX, wherein X is chosen fromhydrogen, alkyl, and heteroalkyl groups, wherein the alkyl andheteroalkyl groups can optionally cyclize with other groups on thecompound, such as R, R1, R3, or with another X group when multiple Xgroups are present.

“Cycloalkyl” or “carbocyclyl” means monocyclic or polycyclic saturatedcarbon rings containing 3-18 carbon atoms. One or two ring carbon atomsin the cycloalkyl ring can optionally be replaced by a —C(O)— group.Examples of cycloalkyl groups include, without limitations, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyland derivatives thereof. A C₃-C₈ cycloalkyl is a cycloalkyl groupcontaining between 3 and 8 carbon atoms. A cycloalkyl group can be fused(e.g., decalin) or bridged (e.g., norbornane).

“Heterocyclyl” or “heterocycloalkyl” monocyclic or polycyclic ringscontaining carbon and heteroatoms taken from oxygen, nitrogen, or sulfurand wherein there is not delocalized π electrons (aromaticity) sharedamong the entire ring carbon or heteroatoms. One or two ring carbonatoms in the heterocycloalkyl ring can optionally be replaced by a—C(O)— group. The heterocycloalkyl ring structure may be substituted byone or more substituents. The substituents can themselves be optionallysubstituted. Examples of heterocyclyl rings include, but are not limitedto, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl,pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl,oxazolidinonyl, and homotropanyl. As used herein, “heterocyclyl” and“heterocycloalkyl” also includes bridged and spirocyclic ring systemswhere at least one atom is a heteroatom. A heterocyclic ring as asubstituent may attach via a ring heteroatom (e.g. “N-linked”) or via aring carbon (e.g. “C-linked”).

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, e.g., C≡N.

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the disclosuremay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumerate, fiunarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate,mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,mucate, napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The terms “administer”, “administering”, or “administration” as used inthis disclosure refer to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

As used herein, the term “neurodegenerative disease” includes, but isnot limited to, Alzheimer's disease and other dementias, Parkinson'sdisease and other synucleinopathies such as Multiple System Atrophy,dementia with Lewy Bodies and PD-related disorders, Prion disease,Corticobasal Degeneration, Frontotemporal Dementia, Posterior CorticalAtrophy, Primary Progressive Aphasia, Progressive Supranuclear Palsy,Pick's disease, Chronic Traumatic Encephelopathy, Dementia Pugilistica,Traumatic Brain Injury, Vascular Dementia, Peripheral Neuropathy andMultiple Sclerosis.

Formula I (and Formulae (Ia), (Ib), and (Ic))

The present disclosure relates to chemical entities chosen fromcompounds of Formula (I) and pharmaceutically acceptable salts,solvates, prodrugs, stereoisomers, and tautomers thereof, capable ofinhibiting USP30, which are useful for the treatment of diseases anddisorders associated with inhibition of USP30. The disclosure furtherrelates to chemical entities chosen from compounds of Formula (T) andpharmaceutically acceptable salts, solvates, prodrugs, stereoisomers,and tautomers thereof, which are useful for inhibiting USP30.

The chemical entities disclosed are chosen from compounds of Formula(I):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, and (C₃-C₆) heterocycloalkylgroups;

n is 0, 1, or 2; wherein, if n is 2, the R groups can combine to form afused ring system with R₁;

R₁ is chosen from 3-6 membered cyclic or heterocyclic groups;

R₂ is chosen from C(X)_(n), S(O)₂, N(X), heteroatom linkers, N(X)S(O)₂,N(X)S(O)₂N(X), carbonylalkyl groups, and carbonylheteroalkyl groups,wherein the alkyl portion of carbonylalkyl and carbonylheteroalkylgroups can optionally cyclize with R, R₁, or R₃:

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R, R₁, or R₃ or with another X group when multiple X groups arepresent;

R₃ is chosen from hydrogen, halogens, alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, heteroalkoxy groups, haloalkoxy groups,carbonylalkyl groups, carbonylheteroalkyl groups, cyclic groups,heterocyclic groups, aryl groups, and heteroaryl groups, wherein anyrings are optionally substituted with 1 or 2 R groups;

R₄ is independently chosen from alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, cycloalkoxy groups, heteroalkoxygroups, haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkylgroups, cyclic groups, heterocyclic groups, aryl groups and heteroarylgroups, wherein any rings are optionally substituted with 1 or 2 Ygroups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups; and

m is 0, 1, or 2.

In some embodiments of Formula (I) above, R is chosen from halogens.

In some embodiments of Formula (I) above, R₁ is chosen fromcyclopropane, cyclobutane, cyclopentane, and cyclohexane. In someembodiments, R₁ is chosen from cyclobutane and cyclopentane. In someembodiments, R₁ is chosen from heterocyclic groups. In some embodiments,R₁ is a pyrrolidine. In some embodiments of Formula (I) above, R₁ is acyclic group. In some embodiments of Formula (I) above, R₁ is aheterocyclic group. In some embodiments of Formula (I) above, R₁ ispreferably cyclobutane.

In some embodiments of Formula (I) above, R₂ is chosen fromcarbonylalkyl and heterocarbonylalkyl groups. In some embodiments, R₂ ischosen from amides, reverse amides, and ureas.

In some embodiments of Formula (I) above, R₂ is chosen fromcarbonylalkyl and heterocarbonylalkyl groups wherein the groupsoptionally cyclize to adjacent groups. In some embodiments, R₂ is chosenfrom amides, reverse amides, and ureas, wherein the amides and reverseamides are optionally cyclized to adjacent groups.

In some embodiments of Formula (I) above, R₂ is a carbonylheteroalkylgroup, wherein the alkyl portion of the carbonylheteroalkyl group canoptionally cyclize with R, R₁, or R₃. In some embodiments of Formula (I)above, R₂ is an amide or reverse amide group. In some embodiments ofFormula (I) above, R₂ is preferably an amide. In some embodiments ofFormula (I) above, R₂ is a reverse amide. In some embodiments of Formula(I) above, R₂ is selected from C(O)N(X) and N(X)C(O). In someembodiments of Formula (I) above, R₂ is preferably C(O)N(X). In someembodiments of Formula (I) above, R₂ is N(X)C(O).

In some embodiments of Formula (I) above, R₃ is chosen from aryl andheteroaryl rings. In some embodiments, R₃ is chosen from thiazole,indenyl, pyrazole, and phenyl rings. In some embodiments, R₃ is chosenfrom cyclic and heterocyclic rings.

In some embodiments R₃ is chosen from thiazole, indenyl, pyrazole,phenyl, benzothiazole, and oxazole rings.

In some embodiments of Formula (I) above, R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R. In someembodiments, R₄ is chosen from alkyl, heteroalkyl, and haloalkyl groups.In some embodiments, R₄ is chosen from aryl and heteroaryl ringsoptionally substituted with 1 or 2 R.

In some embodiments of Formula (I) above, m is 0. In some embodiments, mis 1. In some embodiments, m is 2.

In some embodiments of Formula (I) above, R₁ is a cyclobutane optionallysubstituted with 1 or 2 R; R is chosen from (C₁-C₆) alkyl groups,(C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens; R₂ ischosen from amides or reverse amides; R₃ is chosen from C₁-C₃ alkyllinkers, thiazole, phenyl, benzothiazole, oxazole groups optionallysubstituted with 1 or 2 R; R₄ is chosen from cyclic rings, alkyl groups,and heteroaryl groups optionally substituted with 1 or 2 Y; Y is chosenfrom (C₁-C₆) alkyl groups, (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (I) above, R₁ is a cyclobutane optionallysubstituted with 1 or 2 R; R is chosen from (C₁-C₆) alkyl groups,(C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens; R₂ ischosen from amides and reverse amides that form spirocyclic rings withR₁; R₃ is chosen from thiazole, phenyl, and oxazole groups optionallysubstituted with 1 or 2 R; R₄ is chosen from cyclic rings, alkyl groups,and heteroaryl groups optionally substituted with 1 or 2 Y; Y is chosenfrom (C₁-C₆) alkyl groups, and (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (I) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from aryl andheteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (I) above, R₁ is a cyclobutane, R_(b) ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (I) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from alkyl,heteroalkyl, and haloalkyl groups.

Non-limiting illustrative compounds of the disclosure include:

Example No. Structure Chemical Name Compound 10-1

cis-4-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclohexane-1-carboxamide Compound 10-2

trans-4-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclohexane-1-carboxamide Compound 10-3

(1R,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 10-4

(1R,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide Compound 10-5

(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide Compound 10-6

(1S,3R)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide Compound 10-7

(1R,2S)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 10-8

(1S,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 10-9

(1S,2S)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 1-1

trans-3-(cyanoamino)-N-[5-(oxan-4-yl)- 1,3-thiazol-2-yl]cyclobutane-1-carboxamide Compound 10-10

(1S,3S)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide Compound 10-11

(1R,3R)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide Compound 11-1

trans-2-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclopropane-1-carboxamide Compound 11-2

cis-2-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclopropane-1-carboxamide Compound 2-1

3-(cyanoamino)-N-(5-cyclohexyl-1,3- thiazol-2-yl)azetidine-1-carboxamideCompound 2-2

(3S)-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)pyrrolidine-1-carboxamide Compound 2-3

(3R)-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)pyrrolidine-1-carboxamide Compound 3-1

5-phenyl-N-[(trans)-3- (cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide Compound 4-1

5-phenyl-N-[(cis)-3- (cyanoamino)cyclobutyl]-1,3-thiazole-2- carboxamideCompound 12-1

(1R,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 12-2

(1S,3S)-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-3-yl)cyclopentane-1-carboxamide Compound 12-3

(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 12-4

(1S,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1-carboxamide Compound 5-1

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide Compound 5-2

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide Compound 5-3

cis-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-4

cis-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-5

trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide Compound 5-6

trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide Compound 5-7

trans-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-8

trans-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 12-5

(1S,3S)-3-(cyanoamino)-N-(2,3- dihydro-1H-inden-5-yl)cyclopentane-1-carboxamide Compound 12-6

{[(1S,3S)-3-(4-phenylpiperazine-1-earbonyl)cyclopentyl]amino}carbonitrile Compound 12-7

(1S,3R)-N-(5-tert-butyl-1,3-thiazol-2- yl)-3-(cyanoamino)cyclopentane-1-carboxamide Compound 5-9

cis-3-(cyanoamino)-N-(2,3-dihydro-1H-inden-5-yl)cyclobutane-1-carboxamide Compound 5-10

cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide Compound 5-11

{[cis-3-(4-phenylpiperazine-1- carbonyl)cyclobutyl]amino}carbonitrileCompound 5-12

trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-carboxamide Compound 5-13

trans-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide Compound 5-14

trans-3-(cyanoamino)-N-[4-(morpholin-4-yl)phenyl]cyclobutane-1-carboxamide Compound 12-8

{[(3S)-1-[2-(2,3-dichlorophenyl)-1,3- thiazole-4-carbonyl]pyrrolidin-3-yl]amino}carbonitrile Compound 12-9

({1-[2-(2,4-dichlorophenyl)-1,3- thiazole-4-carbonyl]piperidin-4-yl}amino)carbonitrile

Any of the features disclosed above in the context of the compounds ofFormula (I) may also be applied to any of the compounds of Formulae(Ia), (Ib), (Ic), (II), and (III) disclosed herein.

Formula (Ia)

In any of the embodiments of Formula (I) disclosed above, the compoundof Formula (I) may be a compound of Formula (Ia) as described hereinabove. The compounds of Formula (Ia) correspond to compounds of Formula(I) wherein R₁ is a 4-membered cyclic or heterocyclic group.

In some embodiments of Formula (Ia) above, R is chosen from halogens

In some embodiments of Formula (Ia), R₁ is a cyclic group. In someembodiments of Formula (Ia), R₁ is a heterocyclic group. In someembodiments of Formula (Ia), R₁ is preferably cyclobutane.

In some embodiments of Formula (Ia), R₂ is chosen from carbonylalkyl andheterocarbonylalkyl groups. In some embodiments of Formula (Ia), R₂ ischosen from amides, reverse amides, and ureas.

In some embodiments of Formula (Ia), R₂ is chosen from carbonylalkyl andheterocarbonylalkyl groups wherein the groups optionally cyclize toadjacent groups. In some embodiments, R₂ is chosen from amides, reverseamides, and ureas, wherein the amides and reverse amides are optionallycyclized to adjacent groups.

In some embodiments of Formula (I) above, R₂ is a carbonylheteroalkylgroup, wherein the alkyl portion of the carbonylheteroalkyl group canoptionally cyclize with R, R₁, or R₃. In some embodiments of Formula(Ia), R₂ is an amide or reverse amide group. In some embodiments ofFormula (Ia), R₂ is preferably an amide. In some embodiments of Formula(Ia), R₂ is a reverse amide. In some embodiments of Formula (Ia), R₂ isselected from C(O)N(X) and N(X)C(O). In some embodiments of Formula(Ia), R₂ is preferably C(O)N(X). In some embodiments of Formula (Ia), R₂is N(X)C(O).

In some embodiments of Formula (Ia), R₃ is chosen from aryl andheteroaryl rings. In some embodiments of Formula (Ia), R₃ is chosen fromthiazole, indenyl, pyrazole, and phenyl rings. In some embodiments ofFormula (Ia), R₃ is chosen from cyclic and heterocyclic rings.

In some embodiments of Formula (Ia), R₃ is chosen from thiazole,indenyl, pyrazole, phenyl, benzothiazole, and oxazole rings.

In some embodiments of Formula (Ia), R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R. In someembodiments of Formula (Ia), R₄ is chosen from alkyl, heteroalkyl, andhaloalkyl groups. In some embodiments of Formula (Ia), R₄ is chosen fromaryl and heteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ia), m is 0. In some embodiments ofFormula (Ia), m is 1. In some embodiments of Formula (Ia), m is 2.

In some embodiments of Formula (Ia) above, R₁ is a cyclobutaneoptionally substituted with 1 or 2 R; R is chosen from (C₁-C₆) alkylgroups, (C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens;R₂ is chosen from amides or reverse amides; R₃ is chosen from C₁-C₃alkyl linkers, thiazole, phenyl, benzothiazole, oxazole groupsoptionally substituted with 1 or 2 R; R₄ is chosen from cyclic rings,alkyl groups, and heteroaryl groups optionally substituted with 1 or 2Y; Y is chosen from (C₁-C₆) alkyl groups, (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (Ia) above, R₁ is a cyclobutaneoptionally substituted with 1 or 2 R; R is chosen from (C₁-C₆) alkylgroups, (C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens:R₂ is chosen from amides and reverse amides that form spirocyclic ringswith R₁; R₃ is chosen from thiazole, phenyl, and oxazole groupsoptionally substituted with 1 or 2 R; R₄ is chosen from cyclic rings,alkyl groups, and heteroaryl groups optionally substituted with 1 or 2Y; Y is chosen from (C₁-C₆) alkyl groups, and (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (Ia) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from aryl andheteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ia) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ia) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from alkyl,heteroalkyl, and haloalkyl groups.

Any of the features disclosed above in the context of the compounds ofFormula (Ia) may also be applied to any of the compounds of Formulae(I), (Ib), (Ic), (II), and (III) disclosed herein.

Formula (Ib)

In any of the embodiments disclosed above, the compound of Formula (I)may be a compound of Formula (Ib) as described herein above. Thecompounds of Formula (Ib) correspond to compounds of Formula (I) whereinR₂ is carbonylheteroalkyl group, wherein the alkyl portion of thecarbonylheteroalkyl group can optionally cyclize with R, R₁, or R₃.

In some embodiments of Formula (Ib) above, R is chosen from halogens

In some embodiments of Formula (Ib), R₁ is a 4-membered cyclic orheterocyclic group. In some embodiments of Formula (Tb), R₁ is a cyclicgroup. In some embodiments of Formula (Ib), R₁ is a heterocyclic group.In some embodiments of Formula (Ib), R₁ is preferably cyclobutane.

In some embodiments of Formula (Ib), R₂ is chosen from amides, reverseamides, and ureas. In some embodiments of Formula (Ib), R₂ is chosenfrom heterocarbonylalkyl groups wherein the group optionally cyclizes toadjacent groups. In some embodiments, R₂ is chosen from amides, reverseamides, and ureas, wherein the amides and reverse amides are optionallycyclized to adjacent groups.

In some embodiments of Formula (Ib) above, R₂ is a carbonylheteroalkylgroup, wherein the alkyl portion of the carbonylheteroalkyl group canoptionally cyclize with R, R₁, or R₃. In some embodiments of Formula(Tb), R₂ is an amide or reverse amide group. In some embodiments ofFormula (Ib), R₂ is preferably an amide. In some embodiments of Formula(Ib), R₂ is a reverse amide. In some embodiments of Formula (Ib), R₂ isselected from C(O)N(X) and N(X)C(O). In some embodiments of Formula(Ib), R₂ is preferably C(O)N(X). In some embodiments of Formula (Tb), R₂is N(X)C(O).

In some embodiments of Formula (Ib), R₃ is chosen from aryl andheteroaryl rings. In some embodiments of Formula (Ib), R₃ is chosen fromthiazole, indenyl, pyrazole, and phenyl rings. In some embodiments ofFormula (Ib), R₃ is chosen from cyclic and heterocyclic rings.

In some embodiments of Formula (Ib), R₃ is chosen from thiazole,indenyl, pyrazole, phenyl, benzothiazole, and oxazole rings.

In some embodiments of Formula (Ib), R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R. In someembodiments of Formula (Ib), R₄ is chosen from alkyl, heteroalkyl, andhaloalkyl groups. In some embodiments of Formula (Ib), R₄ is chosen fromaryl and heteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ib), m is 0. In some embodiments ofFormula (Ib), m is 1. In some embodiments of Formula (Ib), m is 2.

In some embodiments of Formula (Ib) above, R₁ is a cyclobutaneoptionally substituted with 1 or 2 R; R is chosen from (C₁-C₆) alkylgroups, (C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens;R₂ is chosen from amides or reverse amides; R₃ is chosen from C₁-C₃alkyl linkers, thiazole, phenyl, benzothiazole, oxazole groupsoptionally substituted with 1 or 2 R; R₄ is chosen from cyclic rings,alkyl groups, and heteroaryl groups optionally substituted with 1 or 2Y; Y is chosen from (C₁-C₆) alkyl groups, (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (Ib) above, R₁ is a cyclobutaneoptionally substituted with 1 or 2 R; R is chosen from (C₁-C₆) alkylgroups, (C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens;R₂ is chosen from amides and reverse amides that form spirocyclic ringswith R₁; R₃ is chosen from thiazole, phenyl, and oxazole groupsoptionally substituted with 1 or 2 R; R₄ is chosen from cyclic rings,alkyl groups, and heteroaryl groups optionally substituted with 1 or 2Y; Y is chosen from (C₁-C₆) alkyl groups, and (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (Ib) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from aryl andheteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ib) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ib) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from alkyl,heteroalkyl, and haloalkyl groups.

Any of the features disclosed above in the context of the compounds ofFormula (Ib) may also be applied to any of the compounds of Formulae(I), (Ia), (Ic), (II), and (Ill) disclosed herein.

Formula (Ic)

In any of the embodiments disclosed above, the compound of Formula (I)may be a compound of Formula (Ic) as described herein above. Thecompounds of Formula (Ic) correspond to compounds of Formula (I) whereinR₁ is a 4-membered cyclic or heterocyclic group; and R₂ iscarbonylheteroalkyl group, wherein the alkyl portion of thecarbonylheteroalkyl group can optionally cyclize with R, R₁, or R₃.

In some embodiments of Formula (Ic) above, R is chosen from halogens.

In some embodiments of Formula (Ic), R₁ is a cyclic group. In someembodiments of Formula (Ic), R₁ is a heterocyclic group. In someembodiments of Formula (Ic), R₁ is preferably cyclobutane.

In some embodiments of Formula (Ic), R₂ is chosen from amides, reverseamides, and ureas. In some embodiments of Formula (Ic), R₂ is chosenfrom heterocarbonylalkyl groups wherein the group optionally cyclizes toadjacent groups. In some embodiments, R₂ is chosen from amides, reverseamides, and ureas, wherein the amides and reverse amides are optionallycyclized to adjacent groups.

In some embodiments of Formula (Ic), R₂ is an amide or reverse amidegroup. In some embodiments of Formula (Ic), R₂ is preferably an amide.In some embodiments of Formula (Ic), R₂ is a reverse amide. In someembodiments of Formula (Ic), R₂ is selected from C(O)N(X) and N(X)C(O).In some embodiments of Formula (Ic), R₂ is preferably C(O)N(X). In someembodiments of Formula (Ic), R₂ is N(X)C(O).

In some embodiments of Formula (Ic), R₃ is chosen from aryl andheteroaryl rings. In some embodiments of Formula (Ic), R₃ is chosen fromthiazole, indenyl, pyrazole, and phenyl rings. In some embodiments ofFormula (Ic), R₃ is chosen from cyclic and heterocyclic rings.

In some embodiments of Formula (Ic), R₃ is chosen from thiazole,indenyl, pyrazole, phenyl, benzothiazole, and oxazole rings.

In some embodiments of Formula (Ic), R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R. In someembodiments of Formula (Ic), R₄ is chosen from alkyl, heteroalkyl, andhaloalkyl groups. In some embodiments of Formula (Ic), R₄ is chosen fromaryl and heteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ic), m is 0. In some embodiments ofFormula (Ic), m is 1. In some embodiments of Formula (Ic), m is 2.

In some embodiments of Formula (Ic) above, R₁ is a cyclobutaneoptionally substituted with 1 or 2 R; R is chosen from (C₁-C₆) alkylgroups, (C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens;R₂ is chosen from amides or reverse amides; R₃ is chosen from C₁-C₃alkyl linkers, thiazole, phenyl, benzothiazole, oxazole groupsoptionally substituted with 1 or 2 R; R₄ is chosen from cyclic rings,alkyl groups, and heteroaryl groups optionally substituted with 1 or 2Y; Y is chosen from (C₁-C₆) alkyl groups, (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (Ic) above, R₁ is a cyclobutaneoptionally substituted with 1 or 2 R; R is chosen from (C₁-C₆) alkylgroups, (C₁-C₆) haloalkyl groups, (C₁-C₆) alkoxy groups, and halogens;R₂ is chosen from amides and reverse amides that form spirocyclic ringswith R₁; R₃ is chosen from thiazole, phenyl, and oxazole groupsoptionally substituted with 1 or 2 R; R₄ is chosen from cyclic rings,alkyl groups, and heteroaryl groups optionally substituted with 1 or 2Y; Y is chosen from (C₁-C₆) alkyl groups, and (C₃-C₆) cycloalkyl groups.

In some embodiments of Formula (Ic) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from aryl andheteroaryl rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ic) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from cyclic andheterocyclic rings optionally substituted with 1 or 2 R.

In some embodiments of Formula (Ic) above, R₁ is a cyclobutane, R₂ ischosen from carbonylalkyl and heterocarbonylalkyl groups (e.g. amides,reverse amides, and ureas, preferably amides), R₃ is chosen from aryland heteroaryl rings (e.g. thiazole, indenyl, pyrazole, and phenylrings) preferably heteroaryl rings, and R₄ is chosen from alkyl,heteroalkyl, and haloalkyl groups.

Any of the features disclosed above in the context of the compounds ofFormula (Ic) may also be applied to any of the compounds of Formulae(I), (la), (Ib), (II), and (III) disclosed herein.

Non-limiting illustrative compounds of the disclosure include:

Example No. Structure Chemical Name Compound 1-1

trans-3-(cyanoamino)-N-[5-(oxan-4- yl)-1,3-thiazol-2-yl]cyclobutane-1-carboxamide Compound 2-1

3-(cyanoamino)-N-(5-cyclohexyl-1,3- thiazol-2-yl)azetidine-1-carboxamideCompound 3-1

5-phenyl-N-[(trans)-3- (cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide Compound 4-1

5-phenyl-N-[(cis)-3- (cyanoamino)cyclobutyl]-1,3-thiazole- 2-carboxamideCompound 5-1

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide Compound 5-2

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide Compound 5-3

cis-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-4

cis-3-(cyanoamino)-N-(5-phenyl-1,3- thiazol-2-yl)cyclobutane-3-carboxamide Compound 5-5

trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide Compound 5-6

trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide Compound 5-7

trans-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-8

trans-3-(cyanoamino)-N-(5-phenyl-1,3- thiazol-2-yl)cyclobutane-1-carboxamide Compound 5-9

cis-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-carboxamide Compound 5-10

cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide Compound 5-11

{[cis-3-(4-phenylpiperazine-1- carbonyl)cyclobutyl]amino}carbonitrileCompound 5-12

trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-carboxamide Compound 5-13

trans-N-(5-tert-butyl-1,3-thiazol-2-yl)- 3-(cyanoamino)cyclobutane-1-carboxamide Compound 5-14

trans-3-(cyanoamino)-N-[4- (morpholin-4-yl)phenyl]cyclobutane-1-carboxamideand pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

Non-limiting illustrative compounds of the disclosure also include:

Example No. Structure Chemical Name Compound 1-2

(1r,3r)-3-(cyanoamino)-N-(1-methyl- 3-phenyl-1H-pyrazol-5-yl)cyclobutane-1-carboxamide Compound 1-3

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)cyclobutane-1-carboxamide Compound 1-4

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-N-methylcyclobutane-1-carboxamide Compound 1-5

(1r,3r)-N-(5-tert-butyl-1,3-thiazol-2- yl)-3-(cyanoamino)-N-methylcyclobutane-1-carboxamide Compound 1-6

(1r,3r)-3-(cyanoamino)-N-(3- cyclohexyl-1-methyl-1H-pyrazol-5-yl)cyclobutane-1-carboxamide Compound 1-7

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-4-methyl-1,3-thiazol-5-yl)cyclobutane-1-carboxamide Compound 1-8

(1r,3r)-3-(cyanoamino)-N-{2-[2- (propan-2-yloxy)phenyl]-1,3-thiazol-5-yl}cyclobutane-1-carboxamide Compound 1-9

(1r,3r)-3-(cyanoamino)-N-[2-(3,3- difluorocyclobutyl)-1,3-thiazol-5-yl]cyclobutane-1-carboxamide Compound 1-10

(1r,3r)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-11

(1r,3s)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-1-methylcyclobutane-1-carboxamide Compound 1-12

(1r,3r)-3-(cyanoamino)-N-{2-[(1S)- 2,2-dimethylcyclohexyl]-1,3-thiazol-5-yl}cyclobutane-1-carboxamide Compound 1-13

(1r,3r)-3-(cyanoamino)-N-{2-[(1R)- 2,2-dimethylcyclohexyl]-1,3-thiazol-5-yl}cyclobutane-1-carboxamide Compound 1-14

(1r,3r)-N-(4-chloro-2-cyclohexyl- 1,3-thiazol-5-yl)-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-15

(1R,3R)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-2,2-dimethylcyclobutane-1-carboxamide Compound 1-16

(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(methoxymethyl)-1,3-thiazol-2-yl]cyclobutane-1- carboxamide Compound 1-17

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-4-fluoro-1,3-thiazol-5-yl)cyclobutane-1-carboxamide Compound 1-18

(1s,3s)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-19

(1r,3r)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-3-(cyanoamino)cyclobutane-1 carboxamide Compound 1-20

(1r,3r)-N-[4-chloro-3- (trifluoromethyl)phenyl]-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-21

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2R)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide Compound 1-22

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2S)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide Compound 1-23

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2S)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide Compound 1-24

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2R)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide Compound 1-25

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-4-cyclopropyl-1,3-thiazol-2-yl)cyclobutane-1- carboxamide Compound 1-26

(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(1-cyclopropyl-1H-pyrazol-4-yl)-1,3-thiazol-2- yl]cyclobutane-1-carboxamide Compound 1-27

(1r,3r)-3-(cyanoamino)-N-[4- (trifluoromethyl)pyridin-2-yl]cyclobutane-1-carboxamide Compound 1-28

(1r,3r)-3-(cyanoamino)-N-{5-[(2S}- oxan-2-yl]-1,3-thiazol-2-yl}cyclobutane-1-carboxamide Compound 1-29

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-4-methyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide Compound 1-30

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-1-methyl-1H-pyrazol-3-yl)cyclobutane-1-carboxamide Compound 1-31

(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(trifluoromethyl)-1,3-thiazol-2-yl]cyclobutane-1- carboxamide Compound 1-32

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2R)-2-(trifluoromethyl)cyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-carboxamide Compound 1-33

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2S)-2-(trifluoromethyl)cyclohexyl]-1,3- thiazol-2-yl]cyclobutane-1-carboxamide Compound 1-34

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2S)-2-(trifluoromethyl)cyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-carboxamide Compound 1-35

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2R)-2-(trifluoromethyl)cyclohexyl]-1,3- thiazol-2-yl}cyclobutane-1-carboxamide Compound 1-36

(1r,3r)-N-(4-chloro-5-cyclopropyl- 1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-37

(1r,3r)-N-{5-[(2R)- bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-38

(1r,3r)-N-{5-[(2S)- bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-39

(1r,3r)-N-(5-chloro-1-cyclohexyl- 1H-pyrazol-3-yl)-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-40

(1r,3r)-3-(cyanoamino)-N-[5-(3- cyanophenyl)-1,3-thiazol-2-yl]cyclobutane-1-carboxamide Compound 1-41

(1r,3r)-N-[3-(3-chlorophenyl)-1,2- oxazol-5-yl]-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-42

(1r,3s)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)-1-methylcyclobutane-1-carboxamide Compound 1-43

(1r,3r)-N-[5-(3-chlorophenyl)-1,2- oxazol-3-yl]-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-44

(1r,3s)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)-1-methylcyclobutane-1-carboxamide Compound 1-45

(1r,3r)-N-[3-(3-chlorophenyl)-1,2- oxazol-5-yl]-3-(cyanoamino)-N-methylcyclobutane-1-carboxamide Compound 1-46

(1r,3s)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-1-ethylcyclobutane-1-carboxamide Compound 1-47

(1s,3s)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluorocyclobutane-1-carboxamide Compound 1-48

(1r,3r)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluorocyclobutane-1-carboxamide Compound 1-49

(1r,3r)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)-N-methylcyclobutane-1-carboxamide Compound 1-50

(1r,3r)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-3-(cyanoamino)-N-methylcyclobutane-1-carboxamide Compound 1-51

(1r,3r)-3-(cyanoamino)-N-[3-(3- cyanophenyl)-1,2-oxazol-5-yl]cyclobutane-1-carboxamide Compound 1-52

(1r,3r)-N-[5-(3-chlorophenyl)-1,2- oxazol-3-yl]-3-(cyanoamino)-N-methylcyclobutane-1-carboxamide Compound 1-53

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-oxazol-2-yl)cyclobutane-1-carboxamide Compound 1-54

(1r,3r)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-3-(cyanoamino)-1-fluoro-N-methylcyclobutane-1- carboxamide Compound 1-55

(1r,3r)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluoro-N-methylcyclobutane-1- carboxamide Compound 1-56

(1s,3s)-3-(cyanoamino)-1-fluoro-N- {3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}cyclobutane-1- carboxamide Compound 1-57

(1r,3r)-3-(cyanoamino)-1-fluoro-N- {3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}cyclobutane-1- carboxamide Compound 1-58

(1s,3s)-N-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluoro-N-methylcyclobutane-1- carboxamide Compound 1-59

(1s,3s)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-3-(cyanoamino)-1-fluorocyclobutane-1-carboxamide Compound 1-60

(1r,3r)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-3-(cyanoamino)-1-fluorocyclobutane-1-carboxamide Compound 1-61

(1r,3r)-3-(cyanoamino)-N-[3-(2- fluorophenyl)-5-methylphenyl]cyclobutane-1- carboxamide Compound 1-62

(1r,3r)-N-(3-chloro-5- cyclohexylphenyl)-3- (cyanoamino)cyclobutane-1-carboxamide Compound 1-63

(1r,3r)-3-(cyanoamino)-N-[4-fluoro- 3-(piperidin-1-yl)phenyl]cyclobutane-1- carboxamide Compound 1-64

(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)cyclobutane-1-carboxamide Compound 1-65

(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)-1-fluorocyclobutane-1-carboxamide Compound 1-66

(1s,3s)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)-1-fluorocyclobutane-1-carboxamide Compound 1-67

(1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2- yl]methyl}cyclobutane-1- carboxamideCompound 1-68

(1r,3r)-N-[4-(4-chlorophenyl)-1,3- thiazol-2-yl]-3-(cyanoamino)cyclobutane-1- carboxamide Compound 1-69

(1r,3r)-3-(cyanoamino)-N-(3- phenylphenyl)cyclobutane-1- carboxamideCompound 1-70

(1r,3r)-3-(cyanoamino)-N-{[4- (propan-2- yl]phenyl]methyl}cyclobutane-1-carboxamide Compound 1-71

(1r,3r)-3-(cyanoamino)-N-[(1s,4s)-4- tert-butylcyclohexyl]cyclobutane-1-carboxamide Compound 1-72

(1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2- yl]methyl}cyclobutane-1- carboxamideCompound 1-73

(1r,3r)-3-(cyanoamino)-N-[3- (trifluoromethyl)phenyl]cyclobutane-1-carboxamide Compound 3-2

{[1-(2-phenyl-1,3-thiazole-5- carbonyl)-1-azaspiro[3.3]heptan-6-yl]amino}carbonitrile Compound 3-3

3-[4-(1-methyl-1H-pyrazol-4- yl)phenyl]-N-[(1s,3s)-3-(cyanoamino)cyclobutyl]-1,2- oxazole-5-carboxamide Compound 3-4

{[(2r,4s)-5-{3-[4-(1-methyl-1H- prazol-4-yl)phenyl]-1,2-oxazole-5-carbonyl}-5-azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound 3-5

{[(4r,6s)-1-{3-[4-(1-methyl-1H- pyrazol-4-yl)phenyl]-1,2-oxazole-5-carbonyl}-1-azaspiro[3.3]heptan-6- yl]amino}carbonitrile Compound 3-6

3-(3-cyanophenyl)-N-methyl-N- [(1r,3r)-3-(cyanoamino)cyclobutyl]-1,2-oxazole-5-carboxamide Compound 6-1

{[(1r,3r)-3-[(4S)-4-[(5-cyclohexyl- 1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1- yl]cyclobutyl]amino}carbonitrile Compound 7-1

{[(2r,4s)-6-(5-tert-butyl-4-chloro- 1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound 7-2

{[(2s,4r)-6-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound 7-3

{[(2r,4s)-6-(4-chloro-5-cyclohexyl- 1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile Compound 8-1

(1r,3r)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-3-(cyanoamino)-1-methoxycyclobutane-1-carboxamide Compound 9-1

(1s,3s)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1- carboxamide Compound 9-2

(1r,3r)-N-(5-tert-butyl-4-chloro-1,3- thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1- carboxamideand pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof.

Formula II

The disclosure also provides compounds of Formula II:

wherein A, R_(a), R_(b), R_(c), R_(d), R_(e), R_(f), R, R₂, R₃, R₄, R₅,X, Y, and m are as described herein above.

The disclosure provides compounds of Formula (II), wherein preferably Ais CR_(b).

The disclosure provides compounds of Formula (II), wherein R_(a) ishydrogen.

The disclosure provides compounds of Formula (H), wherein R_(b) isselected from hydrogen, halogen, (C₁-C₆) alkyl groups optionallysubstituted with one or more R₅, and (C₁-C₆) alkoxy groups optionallysubstituted with one or more R₅.

The disclosure provides compounds of formula (II), wherein both R_(a)and R_(b) are each hydrogen.

The disclosure provides compounds of Formula (II), wherein each ofR_(c), R_(d), R_(e), and R_(f) is independently selected from the groupconsisting of hydrogen and (C₁-C₆) alkyl groups optionally substitutedwith one or more R₅. In some embodiments of Formula (II), each of R_(c),R_(d), R_(e), and R_(f) in the compounds of Formula (II) is hydrogen.

The disclosure provides compounds of Formula (II) wherein R₂ is selectedfrom amides and reverse amides. The disclosure provides compounds ofFormula (II) wherein R₂ is an amide. The disclosure provides compoundsof Formula (II) wherein R₂ is a reverse amide. The disclosure providescompounds of Formula (II) wherein R₂ is selected from C(O)N(X) andN(X)C(O). The disclosure provides compounds of Formula (II), wherein R₂is preferably C(O)N(X). The disclosure provides compounds of Formula(II), wherein R₂ is N(X)C(O).

In a preferred embodiment of Formula (II), A is CR_(b) and R₂ isselected from amides and reverse amides. In one embodiment A is CR_(b)and R₂ is a reverse amide. More preferably, A is CR_(b) and R₂ is anamide.

In a preferred embodiment of Formula (II), A is CR_(b) and R₂ isselected from C(O)N(X) and N(X)C(O). In one embodiment A is CR_(b) andR₂ is N(X)C(O). More preferably, A is CR_(b) and R₂ is C(O)N(X).

The disclosure provides compounds of Formula (II), wherein X is selectedfrom hydrogen and alkyl groups. In some embodiments of Formula (II) X isH.

The disclosure provides compounds of Formula (II), wherein X is selectedfrom alkyl groups and heteroalkyl groups, and the alkyl and heteroalkylgroups cyclize with R_(b) or R₃.

The disclosure provides compounds of Formula (II) wherein R₃ is selectedfrom the group consisting of aryl having 1 to 3 aromatic rings(including aryl groups optionally substituted with 1 or 2 R groups) andheteroaryl having 1 to 3 aromatic rings (including heteroaryl groupsoptionally substituted with 1 or 2 R groups). In some embodiments ofFormula (II) R₃ is a heteroaryl group having 1 to 3 aromatic rings(including heteroaryl groups optionally substituted with 1 or 2 Rgroups). In some embodiments of Formula (II), R₃ is a heteroaryl grouphaving 1 aromatic ring optionally substituted with 1 or 2 R groups. Insome embodiments of Formula (II) R₃ is a heteroaryl group having 1aromatic ring optionally substituted with 1 or 2 R groups wherein thearomatic ring features two heteroatoms, preferably one nitrogen and onesulphur atom. In some embodiments of Formula (II) R₃ is a heteroarylgroup having 1 aromatic ring optionally substituted with 1 or 2 R groupswherein the aromatic ring is a 5 membered ring featuring one nitrogenand one sulphur atom, preferably a thiazole ring. In some embodiments ofFormula (II) R₃ is chosen from thiazole, indenyl, pyrazole, phenyl,benzothiazole, and oxazole rings.

The disclosure provides compounds of Formula (II), wherein R₄ is acyclic group, e.g. a cycloalkyl group optionally substituted with 1 or 2Y groups. The disclosure provides compounds of Formula (II), wherein R₄is an aryl group optionally substituted with 1 or 2 Y groups. Thedisclosure provides compounds of Formula (II), wherein R₄ is acyclohexyl group or phenyl group. The disclosure provides compounds ofFormula (II) wherein R₄ is a cyclohexyl group. The disclosure providescompounds of Formula (II), wherein R₄ is a phenyl group.

The disclosure provides compounds of Formula (II) wherein, A is CR_(b),R_(b) is selected from hydrogen and (C₁-C₆)alkyl groups, each of R_(a),R_(c), R_(d), R_(e), and R_(f) is hydrogen, R₂ is C(O)N(X), X isselected from hydrogen and alkyl groups, and R₃ is a heteroaryl grouphaving 1 aromatic ring optionally substituted with 1 or 2 R groupswherein the aromatic ring features one nitrogen and one sulphur atom;and R₄ is a cyclic group or aryl group optionally substituted with 1 or2 Y groups.

The disclosure provides compounds of Formula (II) wherein, A is CR_(b),R_(b) is selected from hydrogen and (C₁-C₆)alkyl groups, each of R_(a),R_(c), R_(d), R_(e), and R_(f) is hydrogen, R₂ is C(O)N(X), X isselected from hydrogen and alkyl groups, and R₃ is a thiazole ringoptionally substituted with 1 or 2 R groups; and R₄ is a 6-memberedcyclic group or aryl group optionally substituted with 1 or 2 Y groups.

Any of the features disclosed above in the context of the compounds ofFormula (II) may also be applied to any of the compounds of Formulae(I), (Ia), (Ib), (Ic), and (III) disclosed herein.

Formula III

The disclosure also provides compounds of Formula (III):

wherein R_(a), R_(b), R_(c), R_(d), R_(e), R_(f), R, R₃, R₄, R₅, X, Y,and m are as described herein above.

The disclosure provides compounds of Formula (III), wherein R_(a) ishydrogen.

The disclosure provides compounds of Formula (III), wherein R_(b) isselected from hydrogen, halogen, (C₁-C₆) alkyl groups optionallysubstituted with one or more R₅, and (C₁-C₆) alkoxy groups optionallysubstituted with one or more R₅.

The disclosure provides compounds of formula (III), wherein both R_(a)and R_(b) are each hydrogen.

The disclosure provides compounds of Formula (III), wherein each ofR_(c), R_(d), R_(e), and R_(f) is independently selected from the groupconsisting of hydrogen and (C₁-C₆) alkyl groups optionally substitutedwith one or more R₅. In some embodiments of the disclosure, each ofR_(c), R_(d), R_(e), and R_(f) in the compounds of Formula (III) ishydrogen.

The disclosure provides compounds of Formula (III), wherein X isselected from hydrogen and alkyl groups. In some embodiments of thecompounds of Formula (III) X is H.

The disclosure provides compounds of Formula (III), wherein X isselected from alkyl groups and heteroalkyl groups, and the alkyl andheteroalkyl groups cyclize with R_(b) or R₃.

The disclosure provides compounds of Formula (III) wherein R₃ isselected from the group consisting of aryl having 1 to 3 aromatic rings(including aryl groups optionally substituted with 1 or 2 R groups) andheteroaryl having 1 to 3 aromatic rings (including heteroaryl groupsoptionally substituted with 1 or 2 R groups). In some embodiments of thedisclosure R₃ in the compounds of Formula (III) is a heteroaryl grouphaving 1 to 3 aromatic rings (including heteroaryl groups optionallysubstituted with 1 or 2 R groups). In some embodiments, R₃ is aheteroaryl group having 1 aromatic ring optionally substituted with 1 or2 R groups. In some embodiments R₃ is a heteroaryl group having 1aromatic ring optionally substituted with 1 or 2 R groups wherein thearomatic ring features two heteroatoms, preferably one nitrogen and onesulphur atom. In some embodiments R₃ is a heteroaryl group having 1aromatic ring optionally substituted with 1 or 2 R groups wherein thearomatic ring is a 5 membered ring featuring one nitrogen and onesulphur atom, preferably a thiazole ring. In some embodiments of Formula(III) R₃ is chosen from thiazole, indenyl, pyrazole, phenyl,benzothiazole, and oxazole rings.

The disclosure provides compounds of Formula (III), wherein R₄ is acyclic group, e.g. a cycloalkyl group optionally substituted with 1 or 2Y groups. The disclosure provides compounds of Formula (III), wherein R₄is an aryl group optionally substituted with 1 or 2 Y groups. Thedisclosure provides compounds of Formula (III), wherein R₄ is acyclohexyl group or phenyl group. The disclosure provides compounds ofFormula (III) wherein R₄ is a cyclohexyl group.

The disclosure provides compounds of Formula (III) wherein, R_(b) isselected from hydrogen and (C₁-C₆)alkyl groups, each of R_(a), R_(c),R_(d), R_(e), and R_(f) is hydrogen, X is selected from hydrogen andalkyl groups, and R₃ is a heteroaryl group having 1 aromatic ringoptionally substituted with 1 or 2 R groups wherein the aromatic ringfeatures one nitrogen and one sulphur atom; and R₄ is a cyclic group oraryl group optionally substituted with 1 or 2 Y groups.

The disclosure provides compounds of Formula (III) wherein, R_(b) isselected from hydrogen and (C₁-C₆)alkyl groups, each of R_(a), R_(c),R_(d), R_(e), and R_(f) is hydrogen, X is selected from hydrogen andalkyl groups, and R₃ is a thiazole Ting optionally substituted with 1 or2 R groups; and R₄ is a 6-membered cyclic group or aryl group optionallysubstituted with 1 or 2 Y groups.

Any of the features disclosed above in the context of the compounds ofFormula (III) may also be applied to any of the compounds of Formulae(I), (Ia), (Ib), (Ic), and (II) disclosed herein.

In this disclosure, statements relating to compounds of Formula (I) mayalso be applied to any of the compounds of Formula (Ia), (Ib), (Ic),(II), and (III).

In another embodiment of the disclosure, the compounds of Formula (I)are enantiomers. In some embodiments the compounds are the(S)-enantiomer. In other embodiments the compounds are the(R)-enantiomer. In yet other embodiments, the compounds of Formula (I)may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent disclosure, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the disclosure, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentdisclosure.

The compounds of the disclosure may contain asymmetric or chiralcenters, and, therefore, exist in different stereoisomeric forms. It isintended that all stereoisomeric forms of the compounds of thedisclosure as well as mixtures thereof, including racemic mixtures, formpart of the present disclosure. In addition, the present disclosureembraces all geometric and positional isomers. For example, if acompound of the disclosure incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the disclosure. Each compound herein disclosed includes allthe enantiomers that conform to the general structure of the compound.The compounds may be in a racemic or enantiomerically pure form, or anyother form in terms of stereochemistry. The assay results may reflectthe data collected for the racemic form, the enantiomerically pure form,or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the disclosure may be atropisomers (e.g.,substituted biaryls) and are considered as part of this disclosure.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the disclosure may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the disclosure. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the disclosure.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this disclosure, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the disclosure. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the disclosure.)Individual stereoisomers of the compounds of the disclosure may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present disclosure can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the compounds disclosed herein.

The compounds disclosed herein may form salts which are also within thescope of this disclosure.

The present disclosure relates to compounds which can be inhibitors ofUSP30.

The disclosure provides compounds having a USP30 IC₅₀ (μM) of 1 μM orless. Non-limiting examples of compounds of the disclosure having aUSP30 IC₅₀ (μM) of 1 μM or less include those exemplified in tables A1to A3 below having an activity reported as “+++” or “++++”.

The disclosure provides compounds having a USP30 IC₅₀ (μM) of less than0.5 μM.

The disclosure also provides compounds having a USP30 IC₅₀ (μM) of lessthan 0.1 μM. Non-limiting examples of compounds of the disclosure havinga USP30 IC₅₀ (μM) of 1 μM or less include those exemplified in tables A1to A3 below having an activity reported as “++++”.

The present disclosure is directed to chemical entities chosen fromcompounds as described herein and pharmaceutically acceptable salts,solvates, prodrugs, stereoisomers, and tautomers thereof, andpharmaceutical compositions comprising at least one chemical entitychosen from compounds as described herein, and pharmaceuticallyacceptable salts, solvates, prodrugs, stereoisomers, and tautomersthereof.

In some embodiments of the methods described herein, neurodegenerativedisease is chosen from Alzheimer's disease and other dementias,Parkinson's disease and other synucleinopathies such as Multiple SystemAtrophy, dementia with Lewy Bodies and PD-related disorders, Priondisease, Corticobasal Degeneration, Frontotemporal Dementia, PosteriorCortical Atrophy, Primary Progressive Aphasia, Progressive SupranuclearPalsy, Pick's disease, Chronic Traumatic Encephelopathy, DementiaPugilistica, Traumatic Brain Injury, Vascular Dementia, PeripheralNeuropathy and Multiple Sclerosis.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a chemical entity chosen from compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof and a pharmaceutically acceptablecarrier. The pharmaceutical acceptable carrier may further include anexcipient, diluent, or surfactant.

The disclosed compounds of the disclosure can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

The present disclosure also relates to a pharmaceutical compositioncomprising a compound disclosed herein and a pharmaceutically acceptablecarrier. The pharmaceutical acceptable carrier may further include anexcipient, diluent, additive, or surfactant. The compounds orpharmaceutical compositions of the disclosure may be administered viaany mode of administration for therapeutic agents. These modes includesystemic or local administration such as oral administration. Dependingon the intended mode of administration, the disclosed compounds orcompositions can be in solid dosage form, such as, for example, tablets,or pills or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered using forms well known to those skilled in thepharmaceutical arts.

The compounds of the disclosure can be administered in effective amountsto treat or prevent a disorder and/or prevent the development thereof insubjects.

In one embodiment, the present disclosure relates to a method ofpreparing a pharmaceutical composition of the present disclosure bymixing at least one pharmaceutically acceptable compound of the presentdisclosure, and, optionally, one or more pharmaceutically acceptablecarriers, additives, or excipients. Pharmaceutical compositionscomprising a compound of the disclosure can be prepared according toconventional mixing, granulating or coating methods, respectively, andthe present pharmaceutical compositions can contain from about 0.1% toabout 99%, from about 5% to about 90%, or from about 1% to about 20% ofthe disclosed compound by weight or volume. The dosage forms of thepresent disclosure, may contain a mixture of one or more compounds ofthis disclosure, and may include additional materials known to thoseskilled in the art as pharmaceutical excipients. Stabilizing additivesmay be incorporated into the delivery agent solution. With some drugs,the presence of such additives promotes the stability and dispersibilityof the agent in solution. The stabilizing additives may be employed at aconcentration ranging from about 0.1 and 5% (W/V), preferably about 0.5%(W/V). Suitable, but non-limiting, examples of stabilizing additivesinclude gum acacia, gelatin, methyl cellulose, polyethylene glycol,carboxylic acids and salts thereof, and polylysine. In one embodiment,the stabilizing additives are gum acacia, gelatin and methyl cellulose.

The compounds of the disclosure provided herein are preferablyadministered in a therapeutically effective amount (e.g., an amounthaving a suitable favorable therapeutic index). The amount and frequencyof administration of the compounds of the disclosure and/or thepharmaceutically acceptable salts thereof will be regulated according tothe judgment of the attending clinician considering such factors as age,condition and size of the patient as well as severity of the symptomsmedical condition being treated. The dosage regimen utilizing thedisclosed compound is selected in accordance with a variety of factorsincluding type, species, age, weight, sex and medical condition of thepatient; the severity of the condition to be treated; the route ofadministration: the renal or hepatic function of the patient; and theparticular disclosed compound employed. A physician or veterinarian ofordinary skill in the art can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a chemical entity chosen from compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof and a pharmaceutically acceptablecarrier. The pharmaceutical acceptable carrier may further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedchemical entity, or, in a range of from one amount to another amount inthe list of doses. In one embodiment, the compositions are in the formof a tablet that can be scored.

Method of Synthesizing the Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds disclosed herein may be prepared by methods known in theart of organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order of theirexecution, shall be consistent with the preparation of compounds ofFormula (I).

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula (I). Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present disclosure can be prepared in a number ofways known to those skilled in the art of organic synthesis. By way ofexample, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereof asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. General procedures toprepare compounds of the instant invention are described in GeneralSchemes 1 and 2.

General Procedure: A Boc-protected amino acid can be coupled to an amine(i.e., Z—NH₂) using a standard coupling reagent (i.e., HATU) and base(i.e., DIEA) in a suitable solvent (i.e., DMF). The Boc group can thenbe removed using either TFA or HCl in a suitable solvent (i.e., DCM) toyield the corresponding crude amine salt. Finally, the crude amine saltcan be reacted with cyanogen bromide in an appropriate solvent (i.e.,THF) with excess base (i.e., TEA or NaHCO₃) at a range of temperatures(i.e., −20° C. to 25° C.) to afford the final product afterpurification.

General Procedure. A mono-Boc-protected diamine can be treated with CDIand another amine (i.e., Z—NH₂) in the presence of a base (i.e., DIEA)in a suitable solvent (i.e., DCM) to afford the corresponding ureaintermediate. The Boc group can then be removed using either TFA or HClin a suitable solvent (i.e., DCM) to yield the corresponding crude aminesalt. Finally, the crude amine salt can be reacted with cyanogen bromidein an appropriate solvent (i.e., THF) with excess base (i.e., TEA orNaHCO₃) at a range of temperatures (i.e., −20° C. to 25° C.) to affordthe final product after purification.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Unless otherwise noted, reactions were conductedunder an inert atmosphere of nitrogen. Proton nuclear magnetic resonance(NMR) spectra were obtained on either Bruker or Varian spectrometers at300 or 400 MHz. Spectra are given in ppm (S) and coupling constants, J,are reported in Hertz. Tetramethylsilane (TMS) was used as an internalstandard. Mass spectra were collected using a Waters ZQ Single Quad MassSpectrometer (ion trap electrospray ionization (ESI)). Purity and lowresolution mass spectral data were measured using Waters Acquity i-classultra-performance liquid chromatography (UPLC) system with Acquity PhotoDiode Array Detector, Acquity Evaporative Light Scattering Detector(ELSD) and Waters ZQ Mass Spectrometer. Data was acquired using WatersMassLynx 4.1 software and purity characterized by UV wavelength 220 nm,evaporative light scattering detection (ELSD) and electrospray positiveion (ESI). (Column: Acquity UPLC BEH C18 1.7 μm 2.1×50 mm; Flow rate 0.6mL/min; Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/FormicAcid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient:5-100/B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21 mins.Preparatory HPLC purifications were conducted as designated below. Theabsolute configuration of the separated enantiomers of the compounds inthe examples described herein was occasionally determined. In all othercases the absolute configuration of the separated enantiomers was notdetermined and in those instances the configuration of the resolvedmaterials were arbitrarily assigned as R or S in each case.

Abbreviations used in the following examples and elsewhere herein are:

Abbreviation Name atm atmospheres AcOH acetic acid Boc t-butoxycarbonylCDI 1,1′-Carbonyldiimidazole CDCl₃ deuterated chloroform Cs₂CO₃ cesiumcarbonate DAST Diethylaminosulfur trifluoride DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane, methylenechloride DIEA diisopropylethylamine DMA N,N-dimethylacetamide DMFN,N-dimethylformamide DMSO dimethylsulfoxide DPPA Diphenylphosphorylazide EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ES electrosprayEt₃N triethylamine Et₂O diethyl ether EtOAc ethyl acetate EtOH ethanol hor hr hours H₂O water HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HBTUN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl) uroniumhexafluorophosphate HCl hydrochloric acid HOBt Hydroxybenzotriazole IPAisopropanol K₂CO₃ potassium carbonate LDA Lithium diisopropylamide MeCNacetonitrile MeOH methanol MgSO₄ magnesium sulfate min minutes MS massspectrometry MTBE Methyl tert-butyl ether Na₂CO₃ Sodium carbonate Na₂SO₄sodium sulfate NaH sodium hydride NaHCO₃ sodium bicarbonate NaOH sodiumhydroxide N.D. Not determined NH₄HCO₃ ammonium bicarbonate NH₄OHammonium hydroxide NMP N-methyl-2-pyrrolidone Pd/C palladium on carbonPd(dppf)Cl₂ [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II)Pd(dppf)Cl₂•CH₂Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct pet. ether petroleum etherPhI(OAc)₂ (diacetoxyiodo)benzene prep-HPLC preparatory high pressureliquid chromatography prep-TLC preparatory thin layer chromatography rtRoom temperature RT Retention time RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl RuPhos Pd G3(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)] palladium(II)methanesulfonate SFC Supercritical Fluid Chromatography t-BuOHTert-butanol TBS tert-butyl(dimethyl)silyl TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran

Synthetic Examples of Compounds of Formula (I) Example 1.trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclobutane-1-carboxamide(Compound 1-1)

Step 1. tert-butyl(trans-(tetrahydro-2H-pyran-4-yl)thiazol-2-ylcarbamoyl)cyclobutylcarbamate

A solution of trans-3-(tert-butoxycarbonylamino)cyclobutanecarboxylicacid (169 mg, 0.786 mmol), HATU (298 mg, 0.790 mmol),5-(tetrahydro-2H-pyran-4-yl)thiazol-2-amine (120 mg, 0.650 mmol) andDIEA (0.320 mL, 1.96 mmol) in N,N-dimethylformamide (3 mL) was stirredfor 30 min at 25° C. The reaction was then quenched by the addition ofwater (10 mL). The resulting mixture was extracted with ethyl acetate(3×10 mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by Prep-TLC plate (developing solvent: 20:1dichloromethane/methanol) to afford tert-butyl(trans-(tetrahydro-2H-pyran-4-yl)thiazol-2-ylcarbamoyl)cyclobutylcarbamateas a yellow solid (80.0 mg). LCMS (ES, m/z) 382 [M+H]⁺.

Step 2.trans-3-amino-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)cyclobutanecarboxamide2,2,2-trifluoroacetate

A solution of tert-butyl(trans-(tetrahydro-2H-pyran-4-yl)thiazol-2-ylcarbamoyl)cyclobutylcarbamate(80.0 mg, 0.210 mmol) and trifluoroacetic acid (1 mL) in dichloromethane(3 mL) was stirred for 2 h at 25° C. The resulting mixture wasconcentrated under vacuum to affordtrans-3-amino-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)cyclobutanecarboxamide2,2,2-trifluoroacetate as yellow oil (90.0 mg). LCMS (ES, m/z) 282[M+H]⁺.

Step 3.trans-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclobutane-1-carboxamide

Cyanogen bromide (19.0 mg, 0.180 mmol) was added into a stirringsolution oftrans-3-amino-N-(5-(tetrahydro-2H-pyran-4-yl)thiazol-2-yl)cyclobutanecarboxamide2,2,2-trifluoroacetate (70.0 mg, 0.180 mmol) and TEA (0.074 mL, 0.530mmol) in tetrahydrofuran (5 mL) at −20° C. The resulting solution wasstirred for 30 min at −20° C. The reaction was then quenched by theaddition of water (10 mL). The resulting mixture was extracted withethyl acetate (3×15 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by Prep-HPLC (Column: XBridge BEH130 RP18 OBDColumn, 130 Å, 5 μm, 19 mm*150 mm; Mobile phase, A: water (10 mMNH₄HCO₃) and B: ACN (10% up to 40% over 7 min); Flow rate: 20 mL/min;Detector: 254 & 220 nm) to affordtrans-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclobutane-1-carboxamideas a white solid (5.40 mg). ¹H NMR (300 MHz, DMSO-d₆), S 11.92 (s, 1H),7.22 (s, 1H), 7.19 (s, 1H), 3.92-3.79 (m, 3H), 3.46-3.42 (m, 2H),3.28-3.19 (m, 1H), 3.07-2.98 (m, 1H), 2.47-2.42 (m, 2H), 2.27-2.17 (m,2H), 1.88-1.83 (m, 2H), 1.68-1.55 (m, 2H). LC-MS (ESI) m/z 307.2 [M+H]⁺

The following compounds were synthesized according to General Scheme 1:

Example MS m/z No. Structure Chemical Name [M + H]+ 1H NMR Compound 1-2 

(1r,3r)-3-(cyanoamino)- N-(1-methyl-3-phenyl- 1H-pyrazol-5-yl)cyclobutane-1- carboxamide 296 10.01 (s, 1H), 7.75 (d, J = 8.0 Hz,2H), 7.41-7.37 (m, 2H), 7.30-7.24 (m, 2H), 6.66 (s, 1H), 3.87-3.80 (m,1H), 3.70 (s, 3H), 3.26-3.21 (m, 1H), 2.51-2.47 (m, 2H), 2.29-2.21 (m,2H) Compound 1-3 

(1r,3r)-3-(cyanoamino)- N-(2-cyclohexyl-1,3- thiazol-5-yl)cyclobutane-1- carboxamide 305 11.13 (br s, 1H), 7.31 (s, 1H), 7.22(br s, 1H), 3.85-3.76 (m, 1H), 3.17-3.08 (m, 1H), 2.89-2.79 (m, 1H),2.48-2.39 (m, 2H), 2.27-2.17 (m, 2H), 2.05-1.95 (m, 2H), 1.80-1.70 (m,2H), 1.70-1.61 (m, 1H), 1.51-1.31 (m, 4H), 1.31-1.15 (m, 1H) Compound1-4 

(1r,3r)-3-(cyanoatnino)- N-(2-cyclohexyl-1,3- thiazol-5-yl)-N-methylcyclobutane-1- carboxamide 319 7.56-7.38 (m, 1H), 7.28-7.05 (m,1H), 3.72-3.53 (m, 2H), 3.32 (s, 2H), 3.17-3.05 (m, 1H), 2.97-2.80 (m,1H), 2.46-2.35 (m, 1H), 2.35-2.25 (m, 2H), 2.08-1.87 (m, 3H), 1.80-1.62(m, 3H), 1.51-1.29 (m, 4H), 1.29-1.19 (m, 1H) Compound 1-5 

(1r,3r)-N-(5-tert-butyl- 1,3-thiazol-2-yl)-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide 293 7.33-7.20 (m, 2H), 3.71-3.61 (m,2H), 347 (s, 3H), 2.60-2.51 (m, 2H), 2.35-2.28 (m, 2H), 1.33 (s, 9H)Compound 1-6 

(1r,3r)-3-(cyanoamino)- N-(3-cyclohexyl-1- methyl-1H-pyrazol-5-yl)cyclobutane-1- carboxamide 302 9.80 (br s, 1H), 7.22 (br s, 1H), 6.00(s, 1H), 3.84-3.76 (m, 1H), 3.55 (s, 3H), 3.33-3.15 (m, 1H), 2.50-2.45(m, 3H) 2.25-2.18 (m, 2H), 1.85-1.83 (m, 2H), 1.73-1.72 (m, 2H), 1.65(d, J = 12.8 Hz, 1H), 1.37-1.26 (m, 4H), 1.25-1.15 (m, 1H) Compound 1-7 

(1r,3r)-3-(cyanoamino)- N-(2-cyclohexyl-4- methyl-1,3-thiazol-5-yl)cyclobutane-1- carboxamide 319 10.19 (br s, 1H), 7.22 (br s, 1H),3.90-3.75 (m, 1H), 3.30-3.22 (m, 1H), 2.82-2.75 (m, 1H), 2.43-2.37 (m,2H), 2.25-2.15 (m, 5H), 2.00-1.90 (m, 2H), 1.75-1.70 (m, 2H), 1.70-1.60(m, 1H), 1.43-1.27 (m, 4H), 1.25-1.13 (m, 1H) Compound 1-8 

(1r,3r)-3-(cyanoamino)- N-{2-[2-(propan-2- yloxy)phenyl]-1,3- thiazol-5-yl}cyclobutane-1- carboxamide 357 8.22 (d, J = 7.2 Hz, 1H), 7.60 (s,1H), 7.37-7.33 (m, 1H), 7.22-7.20 (m, 1H), 4.93-4.91 (m, 1H), 3.88-3.84(m, 1H), 3.28-3.12 (m, 1H), 2.51-2.43 (m, 2H), 2.33-2.08 (m, 2H), 1,43(d, J = 5.6 Hz, 6H) Compound 1-9 

(1r,3r)-3-(cyanoamino)- N-[2-(3,3- difluomcyclobutyl)-1,3- thiazol-5-yl]cyclobutane-1- carboxamide 313 11.28 (br s, 1H), 7.39 (s, 1H), 7.24(br s, 1H), 3.82 (s, 1H), 3.73-3.64 (m, 1H), 3.20-3.10 (m, 1H),3.09-2.97 (m, 1H), 2.95-2.77 (m, 1H), 2.86 (s, 2H), 2.45 (s, 2H),2.29-2.19 (m, 2H Compound 1-10

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide 339, 341 12.10 (br s, 1H), 7.22 (d, J = 5.5Hz, 1H), 3.85-3.74 (m, 1H), 3.27-3.16 (m, 1H), 2.86-2.76 (m, 1H),2.48-2.41 (m, 2H), 2.28-2.16 (m, 2H), 1.92-1.82 (m, 2H), 1.82-1.72 (m,2H), 1.71-1.63 (m, 1H), 1.42-1.17 (m, 5H) Compound 1-11

(1r,3s)-3-(cyanoamino)- N-(2-cyclohexyl-1,3- thiazol-5-yl)-1-methylcyclobutane-1- carboxamide 319 11.83 (br s. 1H), 7.17 (s, 2H),3.50-3.46 (m, 1H), 2.86-2.73 (m, 3H), 1.94-1.89 (m, 4H), 1.77-1.67 (m,3H), 1.44 (s, 3H), 1.40-1.35 (m, 4H), 1.26-1.20 (m, 1H) Compound 1-12

(1r,3s)-3-(cyanoamino)- N-{2-[(1S)-2,2- dimethylcyclohexyl]-1,3-thiazol-5- yl}cyclobutane-1- carboxamide 333 11.15 (br s, 1H), 7.35(s, 1H), 7.23 (br s, 1H), 3.90-3.78 (m, 1H), 3.19-3.09 (m, 1H),2.77-2.69 (m, 1H), 2.49-2.40 (m, 2H), 2.29-2.17 (m, 2H), 1.87-1.72 (m,2H), 1.70-1.61 (m, 1H), 1.55-1.43 (m, 3H), 1.36-1.21 (m, 2H), 0.87 (d, J= 9.4 Hz, 6H) Compound 1-13

(1r,3r)-3-(cyanoamino)- N-{2-[(1R)-2,2- dimethylcyclohexyl]-1,3-thiazol-5- yl}cyclobutane-1- carboxamide 333 11.15 (br s, 1H), 7.35(s, 1H), 7.23 (br s, 1H), 3.90-3.78 (m, 1H), 3.19-3.09 (m, 1H),2.77-2.69 (m, 1H), 2.49-2.40 (m, 2H), 2.29-2.17 (m, 2H), 1.87-1.72 (m,2H), 1.70-1.61 (m, 1H), 1.55-1.43 (m, 3H), 1.36-1.21 (m, 2H), 0.87 (d, J= 9.4 Hz, 6H) Compound 1-14

(1r,3r)-N-(4-chloro-2- cyclohexyl-1,3-thiazol- 5-yl)-3-(cyanoamino)cyclobutane-1- carboxamide 339, 341 10.7 (br s, 1H), 7.25 (br s, 1H),3.62-3.58 (m, 1H), 3.09-3.04 (m, 1H), 2.88-2.83 (m, 1H), 2.45-2.39 (m,2H), 2.18-2.10 (m, 2H), 2.00-1.87 (m, 2H), 1.77-1.74 (m, 2H), 1.68-1.65(m, 1H), 1.47-1.31 (m, 4H), 1.26-1.21 (m, 1H). Compound 1-15

(1R,3R)-3- (cyanoamino)-N-(2- cyclohexyl-1,3-thiazol- 5-yl)-2,2-dimethylcyclobutane-1- carboxamide 333 1H-NMR (CD3OD, 400 MHz) δ (ppm):7.11 (s, 1H), 3.46-3.42 (m, 1H), 2.83-2.79 (m, 2H), 2.49-2.41 (m, 1H),2.34-2.27 (m, 1H), 2.05-2.00 (m, 2H), 1.86-1.85 (m, 2H), 1.77-1.74 (m,1H), 1.52-1.40 (m, 4H), 1.38-1.28 (m, 4H), 1.02 (s, 3H). Compound 1-16

(1r,3r)-3-(cyanoamino)- N-[5-cyclohexyl-4- (methoxymethyl)-1,3-thiazol-2- yl]cyclobutane-1- carboxamide 349 11.9 (br s, 1H), 7.23 (brs, 1H), 4.33 (s, 2H), 3.84-3.79 (m, 1H), 3.26-3.19 (m, 4H), 2.97-2.92(m, 1H), 2.48-2.44 (m, 2H), 2.34-2.19 (m, 2H), 1.88-1.85 (m, 2H),1.78-1.76 (m, 2H), 1.71-1.60 (m, 1H), 1.44-1.19 (m, 5H). Compound 1-17

(1r,3r)-3-(cyanoamino)- N-(2-cyclohexyl-4- fluoro-1,3-thiazol-5-yl)cyclobutane-1- carboxamide 323 10.9 (br s, 1H), 7.24 (br s, 1H),3.84-3.80 (m, 1H), 3.27-3.02 (m, 1H), 2.84-2.77 (m, 1H), 2.47-2.42 (m,2H), 2.25-2.20 (m, 2H), 1.99-1.96 (m, 2H), 1.76-1.74 (m, 2H), 1.67-1.64(m, 1H), 1.47-1.31 (m, 4H), 1.27-1.18 (m, 1H). Compound 1-18

(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide 339, 341 11.50 (br s, 1H), 7.22 (br s, 1H),3.67-3.55 (m, 1H), 2.96-2.76 (m, 2H), 2.47-2.37 (m, 2H), 2.20-2.08 (m,2H), 1.92-1.82 (m, 2H), 1.82-1.73 (m, 2H), 1.72-1.65 (m, 1H), 1.42-1.17(m, 5H) Compound 1-19

(1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2- yl)-3-(cyanoamino)cyclobutane-1- carboxamide 313, 315 11.40 (br s, 1H), 7.27 (br s, 1H),3.82-3.78 (m, 1H), 3.22-3.17 (m, 1H), 2.51-2.43 (m, 2H), 2.26-2.20 (m,2H), 1.41 (s, 9H) Compound 1-20

(1r,3r)-N-[4-chloro-3- (trifluoromethyl) phenyl]-3- (cyanoamino)cyclobutane-1- carboxamide 318, 320 10.40 (br s, 1H), 8.24 (s, 1H), 7.83(d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.25 (br s, 1H),3.86-3.79 (m, 1H), 3.18-3.13 (m, 1H), 2.51-2.47 (m, 2H), 2.27-2.20 (m,2H) Compound 1-21

(1r,3r)-3- (cyanoarruno)-N-{5- [(1S,2R)-2- methylcyclohexyl]-1,3-thiazol-2- yl}cyclobutane-1- carboxamide 319 11.87 (br s, 1H), 7.20 (d,J = 5.2. Hz, 1H), 7.14 (s, 1H), 3.86-3.75 (m, 1H), 3.27-3.17 (m, 1H),2.48-2.34 (m, 3H), 2.27-2.16 (m, 2H), 1.88-1.64 (m, 4H), 1.47-1.21 (m,4H), 1.12-0.96 (m, 1H), 0.73 (d, J = 6.4 Hz, 3H) Compound 1-22

(1r,3r)-3-(cycloamino)- N-{5-[(1R,2S)-2- methylcyclohexyl]-1,3-thiazol-2- yl}cyclobutane-1- carboxamide 319 11.87 (br, 1H), 7.20 (d, J= 5.2 Hz, 1H), 7.14 (s, 1H), 3.86-3.75 (m, 1H), 3.27-3.17 (m, 1H).2.48-2.34 (m, 3H), 2.27-2.16 (m, 2H), 1.88-1.64 (m, 4H), 1.47-1.21 (m,4H), 1.12-0.96 (m, 1H), 0.73 (d, J = 6.4 Hz, 3H) Compound 1-23

(1r,3r)-3-(cyanoamino)- N-{5-[(1S,2S)-2- methylcyclohexyl]-1,3-thiazol-2- yl}cyclobutane-1- carboxamide 319 11.88 (br s, 1H), 7.23 (s,1H), 7.11 (s, 1H), 3.88-3.76 (m, 1H), 3.29-3.18 (m, 1H), 3.15-3.03 (m,1H), 2.49-2.41 (m, 2H), 2.27-2.17 (m, 2H), 2.04-1.94 (m, 1H), 1.77-1.46(m, 6H), 1.46-1.34 (m, 2H), 0.75 (d, J = 6.8 Hz, 3H) Compound 1-24

(1r,3r)-3-(cyanoamino)- N-{5-[(1R,2R)-2- methylcyclohexyl]-1,3-thiazol-2- yl}cyclobutane-1- carboxamide 319 11.88 (br s, 1H), 7.23 (s,1H), 7.11 (s, 1H), 3.88-3.76 (m, 1H), 3.29-3.18 (m, 1H), 3.15-3.03 (m,1H), 2.49-2.41 (m, 2H), 2.27-2.17 (m, 2H), 2.04-1.94 (m, 1H), 1.77-1.46(m, 6H), 1.46-1.34 (m, 2H), 0.75 (d, J = 6.8 Hz, 3H) Compound 1-25

(1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-4- cyclopropyl-1,3- thiazol-2-yl)cyclobutane-1- carboxamide 345 11.80 (s, 1H), 7.22 (d, J = 5.6 Hz,1H), 3.80-3.77 (m, 1H), 3.20-3.16 (m, 1H), 3.00-2.91 (m, 1H), 2.45-2.35(m, 2H), 2.25-2.12 (m, 2H), 1.96-1.89 (m, 2H), 1.79-1.68 (m, 3H),1.21-1.41 (m, 5H), 1.79-1.68 (m, 3H), 0.85-0.73 (m, 4H Compound 1-26

(1r,3r)-3-(cyanoamino)- N-[5-cyclohexyl-4-(1- cyclopropyl-1H-pyrazol-4-yl)-1,3- thiazol-2- yl]cyclobutane-1- carboxamide 41111.90-12.05 (m, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.24 (d, J = 4.8 Hz,1H), 3.85-3.80 (m, 2H), 3.24-3.21 (m, 1H), 3.02-2.98 (m, 2H), 2.48-2.43(m, 2H), 2.26-2.19 (m, 2H), 1.94-1.91 (m, 2H), 1.79-1.70 (m, 3H),1.46-1.11 (m, 5H), 1.09-0.96 (m, 4H) Compound 1-27

(1r,3r)-3-(cyanoamino)- N-[4-(trifluoromethyl) pyridin-2-yl]cyclobutane-1- carboxamide 285 11.99 (br s, 1H), 8.59 (d, J = 5.2 Hz,1H), 8.46 (s, 1H), 7.46 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H),3.84-3.78 (m, 1H), 3.29-3.26 (m, 1H), 2.48-2.46 (m, 2H), 2.27-2.20 (m,2H) Compound 1-28

(1r,3r)-3-(cyanoamino)- N-{5-[(2S)-oxan-2-yl]- 1,3-thiazol-2-yl]cyclobutane-1- carboxamide 307 11.97 (br s, 1H), 7.30 (s, 1H), 7.23(br s, 1H), 4.57-4.55 (m, 1H), 3.96-3.93 (m, 1H), 3.84-3.81 (m, 1H),3.56-3.46 (m, 1H), 3.27-3.22 (m, 1H), 2.51-2.44 (m, 2H), 2.33-2.19 (m,2H), 1.90-1.84 (m, 2H), 1.70-1.50 (m, 4H) Compound 1-29

(1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-4- methyl-1,3-thiazol-2-yl)cyclobutane-1- carboxamide 319 7.26 (br s, 1H), 3.85-3.77 (m, 1H),3.22-3.16 (m, 1H), 2.81-2.75 (m, 1H), 2.52-2.41 (m, 2H), 2.25-2.19 (m,2H), 2.17 (s, 1H), 1.86-1.80 (m, 2H), 1.80-1.70 (m, 2H), 1.70-1.60 (m,1H), 1.40-1.20 (m, 5H) Compound 1-30

(1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-1- methyl-1H-pyrazol-3-yl)cyclobutane-1- carboxamide 302 10.23 (br s, 1H), 7.30-6.80 (br s,1H), 6.30 (s, 1H), 3.82-3.79 (m, H), 3.63 (s, 3H), 3.11-3.07 (m, 1H),2.65-2.59 (m, 1H), 2.41-2.35 (m, 2H), 2.19-2.12 (m, 2H), 1.87-1.83 (m,2H), 1.78-1.75 (m, 2H), 1.71-1.68 (m, 1H), 1.43-1.20 (m, 5H) Compound1-31

(1r,3r)-3-(cyanoamino)- N-[5-cyclohexyl-4- (trifluoromethyl)-1,3-thiazol-2- yl]cyclobutane-1- carboxamide 373 7.24 (s, 1H), 3.84-3.76 (m,1H), 3.27-3.14 (m, 1H), 3.13-3.00 (m, 1H), 2.48-2.45 (m, 2H), 2.28-2.17(m, 2H), 1.97-1.87 (m, 2H), 1.83-1.73 (m, 2H), 1.73-1.64 (m, 1H),1.44-1.29 (m, 4H) Compound 1-32

(1r,3r)-3-(cyanoamino)- N-{5-[(1S,2R)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol- 2-yl}cyclobutane-1- carboxamide 373 11.57-11.08(br s, 1H), 7.22-7.21 (br s, 1H), 4.90-4.85 (m, 1H), 4.36-4.31 (m, 1H),3.79-3.70 (m, 1H), 3.39-3.33 (m, 1H), 3.16-3.11 (m, 1H), 2.43-2.37 (m,2H), 2.21-2.17 (m, 4H), 2.08-1.95 (m, 1H), 1.80-1.70 (m, 1H), 1.59-1.42(m, 3H), 1.29-1.24 (m, 1H) Compound 1-33

(1r,3r)-3-(cyanoamino)- N-{5-[(1R,2S)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol- 2-yl}cyclobutane-1- carboxamide 373 11.32 (brs. 1H), 7.22-7.21 (br s, 1H), 4.76-4.71 (m, 1H), 4.53-4.48 (m, 1H),3.79-3.70 (m, 1H), 3.15-3.10 (m, 1H), 3.04-2.97 (m, 1H), 2.40-2.37 (m,3H), 2.40-2.37 (m, 3H), 2.22-2.14 (m, 2H), 2.02-1.90 (m, 2H), 1.77-1.74(m, 1H), 1.68-1.52 (m, 2H), 1.49-1.43 (m, 1H), 1.30-1.24 (m, 1H)Compound 1-34

(1r,3r)-3-(cyanoamino)- N-{5-[(1S,2S)-2- (trifluoromethyl)cyclohexyl-1-1,3- thiazol-2- yl}cyclobutane-1- carboxamide 373 11.28 (brs, 1H), 7.22 (br s, 1H), 4.91-4.85 (m, 1H), 4.36-4.31 (m, 1H), 3.79-3.70(m, 1H), 3.41-3.35 (m, 1H), 3.16-3.11 (m, 1H), 2.40-2.37 (m, 2H),2.21-2.08 (m, 4H), 1.99-1.95 (m, 1H), 1.77-1.73 (m, 1H), 1.59-1.42 (m,3H), 1.33-1.24 (m, 1H) Compound 1-35

(1r,3r)-3-(cyanoamino)- N-{5-[(1R,2R)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol- 2-yl}cyclobutane-1- carboxamide 373 11.20 (brs, 1H), 7.22. (br s, 1H), 4.76-4.71 (m, 1H), 4.53-4.48 (m, 1H),3.76-3.72 (m, 1H), 3.15-3.10 (m, 1H), 3.06-2.90 (m, 1H), 2.40-2.37 (m,3H), 2.26-2.08 (m, 2H), 2.02-1.90 (m, 2H), 1.77-1.74 (m, 1H), 1.67-1.60(m, 2H), 1.52-1.43 (m, 1H), 1.30-1.24 (m, 1H) Compound 1-36

(1r,3r)-N-(4-chloro-5- cyclopropyl-1,3- thiazol-2-yl)-3- (cyanoamino)cyclobutane-1- carboxamide 297, 299 12.19 (br s, 1H), 7.24 (br s, 1H),3.82-3.76 (m, 1H), 3.24-3.18 (m, 1H), 2.50-2.42 (m, 2H), 2.26-2.18 (m,2H), 2.00-1.90 (m, 1H), 1.10-1.00 (m, 2H), 1.70-1.60 (m, 2H) Compound1-37

(1r,3r)-N-{5-[(2R)- bicyclo[2.2.2]octan-2- yl]-1,3-thiazol-2-yl}-3-(cyanoamino) cyclobutane-1- carboxamide 331 7.25 (br s, 1H), 7.22 (s,1H), 3.84-3.79 (m, 1H), 3.25-3.20 (m, 1H), 3.15-3.11 (m, 1H), 2.51-2.43(m, 2H), 2.25-2.18 (m, 2H), 2.05-2.00 (m, 1H), 1.70-1.56 (m, 11H)Compound 1-38

(1r,3r)-N-{5-[(2S)- bicyclo[2.2.2]octan-2- yl]-1.3-thiazol-2-yl}-3-(cyanoamino) cyclobutane-1- carboxamide 331 7.25 (br s, 1H), 7.22 (s,1H), 3.86-3.77 (m, 1H), 3.25-3.21 (m, 1H), 3.15-3.11 (m, 1H), 2.51-2.43(m, 2H), 2.25-2.18 (m, 2H), 2.05-2.00 (m, 1H), 1.70-1.61 (m, 11H)Compound 1-39

(1r,3r)-N-(5-chloro-1- cyclohexyl-1H-pyrazol- 3-yl)-3-(cyanoamino)cyclobutane-1- carboxamide 322, 324 10.60 (br s, 1H), 7.20 (br s, 1H),6.57 (s, 1H), 4.23-4.15 (m, 1H), 3.84-3.77 (m, 1H), 3.15-3.08 (m, 1H),2.43-2.37 (m, 2H), 2.20-2.12 (m, 2H), 1.82-1.74 (m, 4H), 1.73-1.65 (m,3H), 1.45-1.35 (m, 2H), 1.20-1.10 (m, 1H) Compound 1-40

(1r,3r-3-(cyanoamino)- N-[5-(3-cyanophenyl)- 1,3-thiazol-2-yl]cyclobutane-1- carboxamide 324 12.27 (br s, 1H), 8.17 (s, 1H), 8.06(s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.63 (t, J= 8.0 Hz, 1H), 7.28 (br s, 1H), 3.87-3.80 (m, 1H), 3.31-3.28 (m, 1H),2.55-2.52 (m, 1H), 2.52-2.49 (m, 1H), 2.30-2.23 (m, 2H) Compound 1-41

(1r,3r)-N-[3-(3- chlomphenyl)-1,2- oxazol-5-yl]-3- (cyanoamino)cyclobutane-1- carboxamide 317, 319 11.75 (br s, 1H), 7.92 (s, 1H), 7.83(d, J = 7.2 Hz, 1H), 7.59-7.52 (m, 2H), 7.26 (br s, 1H), 6.85 (s, 1H),3.85-3.77 (m, 1H), 3.26-3.19 (m, 1H), 2.53-2.49 (m, 1H), 2.49-2.47 (m,1H), 2.29-2.21 (m, 2H) Compound 1-42

(1r,3s)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)-1-methylcyclobutane-1- carboxamide 305 12.06 (s, 1H), 7.24 (d, J = 6 Hz,1H), 6.72 (s, 1H), 3.66-3.56 (m, 1H), 2.95-2.87 (m, 1H), 2.68-2.56 (m,1H), 2.45-2.41 (m, 2H), 2.19-2.12 (m, 2H), 1.93-1.84 (m, 2H), 1.79-1.68(m, 3H), 1.45-1.27 (m, 4H), 1.26-1.13 (m, 1H) Compound 1-43

(1r,3r)-N-1-5-(3- chlorophenyl)-1,2- oxazol-3-yl]-3- (cyanoamino)cyclobutane-1- carboxamide 317, 319 11.09 (br s, 1H), 7.99 (s, 1H),7.88-7.85 (m, 1H), 7.58-7.57 (m, 2H), 7.17-7.52 (m, 1H), 7.25-7.23 (brs, 1H), 3.83-3.79 (m, 1H), 3.23-3.21 (m, 1H), 2.48-2.45 (m, 2H),2.27-2.20 (m, 2H) Compound 1-44

(1r,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-1-methylcyclobutane-1- carboxamide 353, 355 12.19 (br s, 1H)7.19-7.18(br s, 1H), 3.52-3.44 (m, 1H), 2.85-2.80 (m, 3H), 1.94-1.89 (m, 4H),1.79-1.70 (m, 2H), 1.70-1.67 (m, 1H), 1.43 (s, 3H), 1.39-1.30 (m, 4H),1.30-1.20 (m, 1H) Compound 1-45

(1r,3r)-N-[3-(3- chlorophenyl)-1,2- oxazol-5-yl]-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide 331, 333 7.94 (s, 1H), 7.86 (d, J = 7.2Hz, 1H), 7.60-7.57 (m, 2H), 7.23 (br s, 1H), 7.01 (s, 1H), 3.80-3.40 (m,5H), 2.60-2.40 (m, 2H), 2.30-2.20 (m, 2H) Compound 1-46

(1r,3s)-3-(cyanoamino)- N-(2-cyclohexyl-1,3- thiazol-5-yl)-1-ethylcyclobutane-1- carboxamide 333 10.92 (br s, 1H), 7.40 (s, 1H), 7.21(br s 1H), 3.40-3.38 (m, 1H), 2.86-2.82 (m, 1H), 2.78-2.73 (m, 2H),2.01-1.67 (m, 9H,1.52-1.36 (m, 4H), 1.32-1.22 (m, 1H), 0.71 (t, J = 7.2Hz, 3H) Compound 1-47

(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-1-fluorocyclobutane-1- carboxamide 357, 359 12.63 (br s, 1H), 7.44 (brs, 1H), 4.07-4.00 (m, 1H), 2.87-2.82 (m, 1H), 2.76-2.59 (m, 4H),1.95-1.89 (m, 2H), 1.79-1.77 (m, 2H), 1.73-1.67 (m, 1H), 1.42-1.17 (m,5H) Compound 1-48

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-1-fluorocyclobutane-1- carboxamide 357, 359 12.64 (br s, 1H), 7.47 (brs, 1H), 3.52-3.49 (m, 1H), 3.04-2.97 (m, 2H), 2.87-2.82 (m, 1H),2.48-2.42 (m, 2H), 1.92-1.89 (m, 2H), 1.79-1.77 (m, 2H), 1.71-1.67 (m,1H), 1.42-1.17 (m, 5H) Compound 1-49

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-N-methylcyclobutane- 1-carboxamide 353, 355 7.28 (br s, 1H), 3.71-3.63(m, 2H), 3.43 (s, 3H), 2.82-2.77 (m, 1H), 2.58-2.51 (m, 2H), 2.35-2.28(m, 2H), 1.90-1.88 (m, 2H), 1.77-1.72 (m, 2H), 1.70-1.67 (m, 1H),1.42-1.22 (m, 5H) Compound 1-50

(1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2- yl)-3-(cyanoamino)-N-methylcyclobutane-1- carboxamide 327, 329 7.28 (br s, 1H), 3.69-3.63 (m,2H), 3.42 (s, 3H), 2.60-2.51 (m, 2H), 2.35-2.28 (m, 2H), 1.41 (s, 9H)Compound 1-51

(1r,3r-3-(cyanoamino)- N-[3-(3-cyanophenyl)- 1,2-oxazol-5-yl]cyclobutane-1- carboxamide 308 11.80 (br s, 1H), 8.37 (s, 1H), 8.22(d, J = 8.0 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 8.0 Hz, 1H),7.27 (br s, 1H), 6.95 (s, 1H), 3.85-3.80 (m, 1H), 3.26-3.22 (m, 1H),2.55-2.49 (m, 2H), 2.30-2.23 (m, 2H) Compound 1-52

(1r 3r)-N-[5-(3- chlorophenyl)-l.2- oxazol-3-yl]-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide 331, 333 8.01 (s, 1H), 7.89-7.86 (m,1H), 7.61-7.57 (m, 3H), 7.26 (br s, 1H), 3.74-3.69 (m, 1H), 3.59-3.55(m, 1H), 3.32 (s, 3H), 2.52-2.51 (m, 2H), 2.34-2.27 (m, 2H) Compound1-53

(1r,3r)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- oxazol-2- yl)cyclobutane-1-carboxamide 289 7.25 (br s, 2H), 6.91 (s, 1H), 3.78-3.75 (m, 1H),3.22-3.17 (m, 1H), 2.68-2.62 (m, 1H), 2.47-2.40 (m, 2H), 2.34-2.15 (m,2H), 1.92-1.86 (m, 2H), 1.78-1.71 (m, 2H), 1.70-1.64 (m, 1H), 1.40-1.15(m, 5H) Compound 1-54

(1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2- yl)-3-(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide 345, 347 7.40 (br s, 1H),3.51 (s, 3H), 3.50-3.25 (m, 3H) 2.58-2.51 (m, 2H), 1.41 (s, 9H) Compound1-55

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide 370, 373 7.51 (br s, 1H),3.52 (s, 3H), 3.34-3.24 (m, 3H), 2.88-2.84 (m, 1H), 2.58-2.51 (m, 2H),1.92-1.89 (m, 2H), 1.79-1.74 (m, 2H), 1.71-1.68 (m, 1H), 1.43-1.23 (m,5H) Compound 1-56

(1s,3r)-3-(cyanoamino)- 1-fluoro-N-{3-[4- (trifluoromethyl)phenyl]-1H-pyrazol-5- yl}cyclobutane-1- carboxamide 368 13.3 (br s, 1H),10.6 (br s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H),7.45 (br s, 1H), 7.08 (s, 1H), 4.07-4.01 (m, 1H), 2.72-2.61 (m, 4H).Compound 1-57

(1r,3r)-3-(cyanoamino)- 1-fluoro-N-{3-[4- (trifluoromethyl)phenyl]-1H-pyrazol-5- yl}cyclobutane-1- carboxamide 368 13.2 (br s, 1H),10.6 (br s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H),7.47 (br s, 1H), 7.07 (s, 1H), 4.05-3.98 (m, 1H), 3.02-2.97 (m, 2H),2.51-2.42 (m, 2H). Compound 1-58

(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol- 2-yl)-3-(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide 371, 373 751 (br s, 1H),3.52 (s, 3H), 3.34-3.24 (m, 3H), 2.88-2.84 (m, 1H), 2.58-2.51 (m, 2H),1.92-1.89 (m, 2H), 1.79-1.74 (m, 2H), 1.71-1.68 (m, 1H), 1.43-1.23 (m,5H) Compound 1-59

(1s,3s)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2- yl)-3-(cyanoamino)-1-fluorocyclobutane-1- carboxamide 331, 333 12.57 (br s, 1H), 7.43 (br s,1H), 4.07-3.98 (m, 1H), 2.72-2.61 (m, 4H), 1.41 (s, 9H) Compound 1-60

(1r,3r)-N-(5-tert-butyl- 4-chloro-1,3-thiazol-2- yl)-3-(cyanoamino)-1-fluorocyclobutane-1- carboxamide 331, 333 12.57 (br s, 1H), 7.48 (br s,1H), 3.51-3.48 (m, 1H), 3.00-2.97 (m, 2H), 2.50-2.41 (m, 2H), 1.41 (s,9H). Compound 1-61

(1r,3r)-3-(cyanoamino)- N-[3-(2-fluorophenyl)- 5-methylphenyl]cyclobutane-1- carboxamide 324 9.96 (br s, 1H), 7.63 (s, 1H), 7.50-7.,40(m, 3H), 7.33-7.28 (m, 2H), 7.24 (br s, 1H), 7.04 (s, 1H), 3.85-3.80 (m,1H), 3.17-3.12 (m, 1H), 2.49-2.43 (m, 2H), 2.34 (s, 3H), 2.25-2.18 (m,2H). Compound 1-62

(1r,3r)-N-(3-chloro-5- cyclohexylphenyl)-3- (cyanoamino) cyclobutane-1-carboxamide 332, 334 10.0 (br s, 1H), 7.62 (s, 1H), 7.35 (s, 1H), 7.24(br s, 1H), 6.95 (s, 1H), 3.85-3.80 (m, 1H), 3.15-3.08 (m, 1H),2.48-2.42 (m, 3H), 2.24-2.17 (m, 2H), 1.78-1.68 (m, 5H), 1.40-1.20 (m,5H). Compound 1-63

(1r,3r)-3-(cyanoamino)- N-[4-fluoro-3- (piperidin-1-yl)phenyl]cyclobutane-1- carboxamide 317 9.85 (br s, 1H), 7.37 (dd, J = 8.0, 2.4Hz, 1H), 7.17--7.13 (m, 1H), 7.04--6.99 (m, 1H), 3.84-3.80 (m, 1H),3.12-3.07 (m, 1H), 2.94-2.92 (m, 4H), 2.48-2.42 (m, 2H), 2.21-2.18 (m,2H), 1.69-1.64 (m, 4H), 1.54-1.51 (m, 2H). Compound 1-64

(1r,3r)-3-(cyanoamino)- N-(7-cyclobutoxy-1,3- benzothiazol-2-yl)cyclobutane-1- carboxamide 343 7.35-7.30 (m, 2H), 6.74-6.72 (m, 1H),4.89-4.82 (m, 1H), 3.84-3.70 (m, 1H), 3.32-3.25 (m, 1H), 2.49-2.45 (m,4H), 2.30-2.22 (m, 2H), 2.14-2.09 (m, 1H), 0.86-0.79 (m, 1H), 0.74-0.65(m, 1H). Compound 1-65

(1r,3r)-3-(cyanoamino)- N-(7-cyclobutoxy-1,3- benzothiazol-2-yl)-1-fluorocyclobutane-1- carboxamide 361 7.45 (br s, 1H), 7.34-7.32 (m, 2H),6.75-6.74 (m, 1H), 4.90-4.87 (m, 1H), 3.62-3.57 (m, 1H), 3.08-2.98 (m,2H), 2.47-2.42 (m, 4H), 2.15-2.08 (m, 2H), 1.85-1.82 (m, 1H), 1.72-1.65(m, 2H). Compound I-66

(1s,3s)-3- (cyanoamino)-N-(7- cyclobutoxv-1,3- benzothiazol-2-yl)-1-fluorocyclobutane-1- carboxamide 361 7.16-7.14 (m, 2H), 6.63-6.54 (m,2H), 6.09 (br s, 1H), 4.83-4.80 (m., 1H), 3.95-3.92 (m, 1H), 2.70-2.58(m, 4H), 2.47-2.33 (m, 2H), 2.14-2.09 (m, 2H), 1.83-1.81 (m, 1H),1.70-1.63 (m, 2H). Compound 1-67

(1r,3r)-3-(cyanoamino)- N-{[(1R,2R,5R)-6,6- dimethylbicyclo[3.1.1]heptan-2-yl]methyl} cyclobutane-1- carboxamide 276 Compound 1-68

(1r,3r)-N-[4-(4- chlorophenyl)-1,3- thiazol-2-yl]-3- (cyanoamino)cyclobutane-1- carboxamide 333 Compound 1-69

(1r,3r)-3-(cyanoamino)- N-(3-phenylphenyl) cyclobutane-1- carboxamide292 Compound 1-70

(1r,3r)-3-(cyanoamino)- N-{[4-(propan-2- yl)phenyl]methyl}cyclobutane-1- carboxamide 272 Compound 1-71

(1r,3r)-3-(cyanoamino)- N-[(1s,4s)-tert- butylcyclohexyl] cyclobutane-1-carboxamide 278 Compound 1-72

(1r,3r)-3-(cyanoamino)- N-(1R,2R,5R)-6,6- dimethylbicyclo[3.1.1]heptan-2-yl]methyl} cyclobutane-1- carboxamide 276 Compound 1-73

(1r,3r)-3-(cyanoamino)- N-[3-(trifluoromethyl) phenyl]cyclobutane-1-carboxamide 284

Example 2-1.3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)azetidine-1-carboxamide(Compound 2-1)

Step 1. tert-butyl(1-((5-cyclohexylthiazol-2-yl)carbamoyl)azetidin-3-yl)carbamate

Into a 50 mL round-bottom flask was placed 5-cyclohexylthiazol-2-amine(300 mg, 1.65 mmol), dichloromethane (5 mL) and triethylamine (833 mg,8.23 mmol). This was followed by the addition ofN,N′-carbonyldiimidazole (348 mg, 2.15 mmol). The resulting solution wasstirred for 2 h at room temperature. Then tert-butylazetidin-3-ylcarbamate (369 mg, 2.14 mmol) was added. The resultingsolution was stirred overnight at room temperature. The reaction mixturewas poured into water (5 mL) and then extracted with ethyl acetate (3×10mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography (eluting with 1:1 ethylacetate/petroleum ether) to afford tert-butyl(1-((5-cyclohexylthiazol-2-yl)carbamoyl)azetidin-3-yl)carbamate as ayellow solid. LC-MS (ESI) m/z 381.2[M+H]⁺

Step 2. 3-amino-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide TFASalt

Into a 50 mL round-bottom flask was placed tert-butyl(1-((5-cyclohexylthiazol-2-yl)carbamoyl)azetidin-3-yl)carbamate (190 mg,0.50 mmol), dichloromethane (3 mL) and trifluoroacetic acid (1 mL). Theresulting solution was stirred for 2 h at room temperature. The reactionmixture was concentrated under vacuum. The residue was treated withethyl ether and dried under vacuum to afford3-amino-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide TFA salt asa yellow oil. LC-MS (ESI) m/z 281.2[M+H]⁺

Step 3.3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)azetidine-1-carboxamide

Into a 50 mL round-bottom flask was placed3-amino-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamide TFA salt(160 mg, 0.41 mmol), dichloromethane (5 mL), potassium carbonate (169mg, 1.22 mmol) and cyanogen bromide (44 mg, 0.42 mmol). The resultingsolution was stirred for 2 h at room temperature. The reaction mixturewas poured into water (5 mL) and then extracted with ethyl acetate (3×10mL). The organic layers were combined, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 130 Å, 5μm, 19 mm×150 mm; Mobile phase: water (10 mM NH₄HCO₃), MeCN (30% MeCN upto 50% over 10 min); Flow rate: 20 mL/min; Detector: 254 & 220 nm) toafford 3-cyanamido-N-(5-cyclohexylthiazol-2-yl)azetidine-1-carboxamideas a white solid. 1H NMR (300 MHz, DMSO-d₆) δ 6.96 (s, 1H), 4.43-4.38(m, 2H), 4.21-4.10 (m, 3H), 2.77-2.73 (m, 1H), 1.81 (s, 4H), 1.45-1.32(m, 7H). LC-MS (ESI) m/z 306.2[M+H]⁺

Example 3-1,5-phenyl-N-[(trans)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide(Compound 3-1)

Step 1. tert-butyl((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate

Into a 100 mL round-bottom flask was placed 5-bromothiazole-2-carboxylicacid (300 mg, 1.41 mmol), N,N-dimethylformamide (5 mL), tert-butylN-[(trans)-3-aminocyclobutyl]carbamate (270 mg, 1.42 mmol),N,N-diisopropylethylamine (560 mg, 4.33 mmol) and HATU (661 mg, 1.74mmol). The resulting solution was stirred for 1 h at room temperature.The reaction mixture was poured into water (5 mL) and then extractedwith ethyl acetate (3×10 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by prep-TLC (eluting with 1:1 ethylacetate/petroleum ether) to afford tert-butyl((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate as ayellow solid. LC-MS (ESI) m-z 320.0, 322.0 [M+H−tBu]⁺

Step 2. tert-butyl((trans)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate

Into a 100 mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl((trans)-3-(5-bromothiazole-2-carboxamido)cyclobutyl)carbamate (200 mg,0.51 mmol), 1,4-dioxane (15 mL), water (5 mL), phenylboronic acid (78mg, 0.63 mmol, 1.23), potassium carbonate (219 mg, 1.58 mmol) andPd(dppf)Cl₂ (39 mg, 0.05 mmol). The resulting mixture was stirredovernight at 80° C. After cooling to room temperature, the reactionmixture was poured into water (10 mL) and then extracted with ethylacetate (3×10 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (eluting with 1:1ethyl acetate/petroleum ether) to afford tert-butyl((trans)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate as awhite solid. LC-MS (ESI) m/z 374.2 [M+H]⁺

Step 3. N-((trans)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFASalt

Into a 50 mL round-bottom flask was placed tert-butyl((trans)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate (60 mg,0.15 mmol), dichloromethane (3 mL) and trifluoroacetic acid (0.6 mL).The resulting solution was stirred for 1 h at room temperature. Thereaction mixture was concentrated under vacuum. The residue was treatedwith ethyl ether and dried under vacuum to affordN-((trans)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA salt asa yellow oil. LC-MS (ESI) m/z 274.2 [M+H]⁺

Step 4.5-phenyl-N-[(trans)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide

Into a 50 mL round-bottom flask was placedN-((trans)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA salt(50 mg, 0.12 mmol), tetrahydrofuran (5 mL) and triethylamine (16 mg,0.16 mmol). After cooling to −10° C., to this solution was addedcyanogen bromide (17 mg, 0.16 mmol). The resulting solution was stirredfor 30 min at −10° C. The reaction mixture was poured into water (5 mL)and then extracted with ethyl acetate (3×10 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by prep-HPLC (Column: XBridgeShield RP18 OBD Column, 130 Å, 5 μm. 19 mm×150 mm; Mobile phase: water(10 mM NH₄HCO₃), MeCN (25% MeCN up to 55% over 7 min); Flow rate: 20mL/min; Detector: 254 & 220 nm) to affordN-((trans)-3-cyanamidocyclobutyl)-5-phenylthiazole-2-carboxamide as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.31 (d, J=7.60 Hz, 1H), 8.44(s, 1H), 7.80-7.77 (m, 2H), 7.51-7.41 (m, 3H), 7.22 (s, 1H), 4.56-4.50(m, 1H), 3.85 (d, J=3.20 Hz, 1H), 2.51-2.46 (m, 2H), 2.33-2.08 (m, 2H).LC-MS (ESI) m/z 299.2 [M+H]+

The following compounds were synthesized in a manner analogous toCompound 3-1:

Example MS m/z No. Structure Chemical Name [M + H]+ 1H NMR Compound 3-2

{[1-(2-1,3- thiazolo-5- carbonyl)-1- azaspiro[3.3] heptan-6- yl]amino}carbonitrile 325 8.25 (s, 1H), 8.03-7.98 (m, 2H), 7.57-7.52 (m, 3H),6.52 (s, 1H), 4.43-4.39 (m, 2H), 3.47-3.41 (m, 1H), 3.06-3.01 (m, 2H),2.55-2.42 (m, 4H) Compound 3-3

3-[4-(1-methyl- 1H-pyrazol-4- yl)phenyl]-N- [(1s,3s)-3- (cyanoamino)cyclobutyl]-1.2- oxazole-5- carboxamide 363 1H-NMR (CD3OD, 400 MHz) δ(ppm): 8.09 (s, 1H), 7.92-7.89 (m, 3H), 7.72 (dd, J = 6.8, 2.0 Hz, 2H),7.40 (s, 1H), 4.21-4.17 (m, 1H), 3.97 (s, 3H), 3.56-3.48 (m, 1H),2.81-2.75 (m, 2H), 2.26-2.18 (m, 2H). Compound 3-4

{[(2r,4s)-5-{3-[4- (1-methyl-1H- pyrazol-4- yl)phenyl]-1,2- oxazole-5-carbonyl}-5- azaspiro[3.4] octan-2-yl]amino} carbonitrile 403 1H-NMR(CDCl3, 400 MHz) δ (ppm): 7.85-7.83 (m, 3H), 7.71 (s, 1H), 7.61 (d, J =8.0 Hz, 2H), 7.18 (s, 1H), 4.40-4.34 (m, 1H), 4.00 (s, 3H), 3.96-3.92(m, 2H), 3.47-4.41 (m, 2H), 2.37-2.241 (m, 4H), 1.96-1.91 (m, 2H).Compound 3-5

{[(4r,6s)-1-{3-[4- (1-methyl-1H- pyrazol-4- yl)phenyl]-1,2- oxazole-5-carbonyl}-1- azaspiro[3.3] heptan-6- yl]amino} carbonitrile 389 8.27 (s,1H), 7.98 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H),7.60 (s, 1H), 7.30 (d. J = 6.0 Hz, 1H), 4.46-4.42 (m, 2H), 3.89 (s, 3H),3.48-3.44 (m, 1H), 3.06-3.00 (m, 2H), 2.48-2.42 (m, 4H) Compound 3-6

3-(3-cyanophenyl)- N-methyl-N- [(1r,3r)-3- (cyanoamino) cyclobutyl]-1,2-oxazole-5- carboxamide 322 8.45 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.04(d, J = 7.6 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.71-7.59 (m, 1H), 7.24(br s, 1H), 5.12-5.08 (m, 0.5H), 4.74-4.70 (m, 0.5H), 3.82-3.78 (m, 1H),3.14-3.06 (m, 3H), 2.73-2.60 (m, 2H), 2.45-2.22 (m, 2H)

Example 4-1.5-phenyl-N-[(cis)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide(Compound 4-1)

Step 1. 5-phenylthiazole-2-carboxylic acid

Into a 100 mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed 5-bromothiazole-2-carboxylic acid (1g, 4.71 mmol), phenylboronic acid (707 mg, 5.68 mmol), potassiumcarbonate (2 g, 14.47 mmol), 1,4-dioxane (20 mL), water (2 mL) andPd(dppf)Cl₂ (352 mg, 0.48 mmol). The resulting mixture was stirred for16 h at 80° C. After cooling to room temperature, the reaction mixturewas poured into water (5 mL) and then washed with ethyl ether (2×5 mL).The aqueous layer was acidified to pH 5 with hydrochloric acid (1N) andthen extracted with ethyl acetate (3×20 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to afford 5-phenylthiazole-2-carboxylic acid as a brownsolid. LC-MS (ESI) m/z 206.1 [M+H]⁺

Step 2. tert-butyl((cis)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate

Into a 100 mL round-bottom flask was placed5-phenylthiazole-2-carboxylic acid (120 mg, 0.56 mmol),N,N-dimethylformamide (20 mL), tert-butylN-[(cis)-3-aminocyclobutyl]carbamate (109 mg, 0.57 mmol),N,N-diisopropylethylamine (227 mg, 1.76 mmol) and HATU (267 mg, 0.70mmol). The resulting solution was stirred for 1 h at room temperature.The reaction mixture was poured into water (10 mL) and then extractedwith ethyl acetate (3×20 mL). The organic layers were combined, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by silica gel chromatography (eluting with 1:3ethyl acetate/petroleum ether) to afford tert-butyl((cis)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate as a whitesolid. LC-MS (ESI) m/z 374.2 [M+H]⁺

Step 3. N-(cis)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFASalt

Into a 50 mL round-bottom flask was placed tert-butyl(cis)-3-(5-phenylthiazole-2-carboxamido)cyclobutyl)carbamate (200 mg,0.51 mmol), dichloromethane (5 mL) and trifluoroacetic acid (1 mL). Theresulting solution was stirred for 1 h at room temperature. The reactionmixture was concentrated under vacuum. The residue was treated withethyl ether and dried under vacuum to affordN-(cis)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA salt as ayellow oil. LC-MS (ESI) m/z 274.2 [M+H]⁺

Step 4.5-phenyl-N-[(cis)-3-(cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide

Into a 50 mL round-bottom flask was placedN-(cis)-3-aminocyclobutyl)-5-phenylthiazole-2-carboxamide TFA salt (120mg, 0.29 mmol), tetrahydrofuran (10 mL) and triethylamine (54 mg, 0.53mmol). After cooling to −10° C., to this solution was added cyanogenbromide (56 mg, 0.52 mmol). The resulting solution was stirred for 30min at −10° C. The reaction mixture was poured into water (5 mL) andthen extracted with ethyl acetate (3×10 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by prep-HPLC (Column: XBridgeShield RP18 OBD Column, 130 Å, 5 μm, 19 mm×150 mm; Mobile phase: water(10 mM NH₄HCO₃), MeCN (25% MeCN up to 55% over 7 min); Flow rate: 20mL/min; Detector: 254 & 220 nm) to affordN-(cis)-3-cyanamidocyclobutyl)-5-phenylthiazole-2-carboxamide as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (d, J=7.60 Hz, 1H), 8.43 (s,1H), 7.78 (d, J=7.20 Hz, 2H), 7.51-7.43 (m, 3H), 7.17 (d, J=4.40 Hz,1H), 4.06-4.04 (m, 1H), 3.39-3.33 (m, 1H), 2.56-2.50 (m, 2H), 2.23-2.16(m, 2H). LC-MS (ESI) m/z 299.2 [M+H]⁺

Example 5:cis-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide(Compound 5-3)

Step 1. tert-butylN-[cis-3-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclobutyl]carbamate

To a stirring mixture ofcis-3-[[(tert-butoxy)carbonyl]amino]cyclobutane-1-carboxylic acid (100mg, 0.465 mmol) in DMF (4 mL) was added HATU (212 mg, 0.560 mmol), DIEA(0.230 mL, 1.39 mmol) and 5-cyclohexyl-1,3-thiazol-2-amine (93.0 mg,0.510 mmol) at 25° C. The resulting solution was stirred for 1.5 h at25° C. The resulting mixture was diluted with water (10 mL) andextracted with DCM (3×15 mL). The combined organic layer was washed withbrine (4×30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluting with 1/1 with ethyl acetate/petroleumether) to afford tert-butylN-[cis-3-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclobutyl]carbamateas a white solid (98.0 mg). LCMS (ES, m/z): 380 [M+H]⁺.

Step 2.cis-3-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide2,2,2-trifluoroacetate

A solution of tert-butylN-[(cis)-3-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclobutyl]carbamate(98.0 mg, 0.258 mmol) and TFA (1 mL) in DCM (5 mL) was stirred for 1 hat 25° C. The resulting mixture was concentrated under reduced pressureto givecis-3-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide2,2,2-trifluoroacetate as yellow oil (102 mg). LCMS (ES, m/z): 280[M+H]⁺.

Step 3.cis-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide

To a stirring mixture ofcis-3-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide2,2,2-trifluoroacetate (102 mg, 0.271 mmol) in DMF (2 mL) was added Et₃N(0.072 mL, 0.520 mmol) dropwise at 0° C. Then BrCN (28.0 mg, 0.260 mmol)was added. The mixture was stirred for 2 h at 25° C. and then pouredinto ice/water (5 mL). The resulting mixture was extracted with DCM(3×10 mL). The combined organic layer was washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by Prep-HPLC (Column, KinetexEVO C18 Column, 21.2×150 mm, 5 μm; Mobile phase, A: water (10 mmol/LNH₄HCO₃) and B: ACN (27% up to 46% in 10 min); Detector, UV 254/220 nm).The collected fraction was lyophilized to givecis-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamideas a white solid (14.9 mg). ¹H-NMR (DMSO-da, 400 MHz) δ (ppm): 11.88 (brs, 1H), 7.20 (br s, 1H), 7.14 (s, 1H), 3.67-3.55 (m, 1H), 2.97-2.85 (m,1H), 2.83-2.71 (m, 1H), 2.47-2.36 (m, 2H), 2.20-2.10 (m, 2H), 2.00-1.88(m, 2H), 1.81- 1.71 (m, 2H), 1.71-1.62 (m, 1H), 1.44-1.29 (m, 4H),1.28-1.15 (m, 1H). LCMS (ES, m/z): 305 [M+H]⁺

The following compounds were synthesized according to Example 5:

Example MS m/z No. Structure Chemical Name [M + H]+ Compound 5-1 

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 282.2 [M + H]⁺ Compound 5-2 

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 282.2 [M + H]⁺ Compound 5-4 

cis-3-(cyanoamino)-N-(5-phenyl-1,3- thiazol-2-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 299.1 [M + H]⁺ Compound 5-5 

trans-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-4-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 282.2 [M + H]⁺ Compound 5-6 

trans-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-3-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 282.2 [M + H]⁺ Compound 5-7 

trans-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thazol-2-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 305.2 [M + H]⁺ Compound5-8 

trans-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 299.2 [M + H]⁺ Compound 5-9 

cis-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 256.2 [M + H]⁺ Compound 5-10

cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide LC-MS (ESI) m/z 279.2 [M + H]⁺ Compound 5-11

{[cis-3-(4-phenylpiperazine-1- carbonyl)cyclobutylamino}carbonitrileLC-MS (ESI) m/z 285.3 [M + H]⁺ Compound 5-12

trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-carboxamide LC-MS (ESI) m/z 256.2 [M + H]⁺ Compound 5-13

trans-N-(5-tert-butyl-1,3-thiazol-2-yl)- 3-(cyanoamino)cyclobutane-1-carboxamide LC-MS (ESI) m/z 279.2 [M + H]⁺ Compound 5-14

trans-3-(cyanoamino)-N-[4- (morpholin-4-yl)phenyl]cyclobutane-1-carboxamide LC-MS (ESI) m/z 301.2 [M + H⁺

Example 6:{[(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]amino}formonitrile(Compound 6-1)

Step 1. 1-(2-Amino-1,3-thiazol-5-yl)cyclohexan-1-ol

A solution of n-BuLi (2.5 M in hexane)(200 mL) was added to a solutionof 1,3-thiazol-2-amine (25.0 g, 0.250 mol) in THF (200 mL) at −78° C.and then the mixture was stirred for 15 min at −78° C.Trimethylchlorosilane (54.5 g, 0.500 mol) was added at −78° C. Theresulting mixture was stirred for 30 min at −25° C. A solution of n-BuLi(2.5 M in hexane) (100 mL) was added at −78° C. and the mixture wasstirred for 15 min at −78° C. Cyclohexanone (27.0 g, 0.275 mol) wasadded and the resulting mixture was stirred for an additional 30 min at−78° C. The reaction was quenched with ammonium chloride (200 mL sat.)at −78° C. The resulting mixture was extracted with ethyl acetate (3×200mL). The combined organic layers were washed with brine (200 mL), driedover anhydrous sodium sulfate, filtered and concentrated under vacuum toafford 1-(2-amino-1,3-thiazol-5-yl)cyclohexan-1-ol as a brown solid(26.0 g). LCMS (ES, m/z) 199 [M+H]⁺.

Step 2. 5-Cyclohexyl-1,3-thiazol-2-amine

Triethylsilane (122 g, 1.05 mol) and TFA (90 mL) were added to asolution of 1-(2-amino-1,3-thiazol-5-yl)cyclohexan-1-ol (23.0 g, 115mmol) in DCM (500 mL), and the reaction mixture stirred for 1 h at 25°C. The resulting mixture was concentrated under vacuum. The residue wasre-crystallized from ethyl ether (50 mL). The solids were collected byfiltration to afford 5-cyclohexyl-1,3-thiazol-2-amine as an off-whitesolid (18.0 g). LCMS (ES, m/z): 183 [M+H]⁺.

Step 3. 2-Bromo-5-cyclohexyl-1,3-thiazole

tert-Butyl nitrite (8.83 mL, 81.4 mmol) was added into a stirringmixture of 5-cyclohexyl-1,3-thiazol-2-amine (10.0 g, 54.9 mmol) andCuBr₂ (24.5 g, 108 mmol) in ACN (200 mL) at 0° C. The resulting mixturewas stirred for 1.5 h at 25° C. The reaction was quenched by theaddition of water (100 mL). The solvent was removed under vacuum. Theresidue was extracted with dichloromethane (3×300 mL). The combinedorganic layers were dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 1:10ethyl acetate/petroleum ether) to afford2-bromo-5-cyclohexyl-1,3-thiazole as yellow oil (10.8 g). LCMS (ES,m/z): 246,248 [M+H]⁺.

Step 4. Methyl (3S)-3-[[(benzyloxy)carbonyl]amino]-4-hydroxybutanoate

A solution of(2S)-2-[[(benzyloxy)carbonyl]amino]-4-methoxy-4-oxobutanoic acid (8.00g, 27.1 mmol), NMM (2.88 g, 27.1 mmol), and ethyl chloroformate (4.01 g,35.1 mmol) in THF (50 mL) was stirred for 10 min at −10° C. To the abovemixture was added NaBH₄ (5.38 g, 135 mmol) in one portion at −10° C.Methanol (70 mL) was added dropwise at −10° C., and the resultingmixture was stirred for additional 30 min at 0° C. The solvent wasremoved under vacuum. The pH value of the residue was adjusted to 6 withhydrochloric acid (1 N) at 0° C. The resulting mixture was extractedwith DCM (3×50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified by reverse phase chromatography (Column, C18 silicagel; Mobile phase, A: water (containing 10 mM NH₄HCO₃) and B: ACN (10%to 50% in 10 min); Detector, UV 254/220 nm) to afford methyl(3S)-3-[[(benzyloxy)carbonyl]amino]-4-hydroxybutanoate as colorless oil(3.00 g). LCMS (ES, m/z) 268 [M+H]⁺.

Step 5. Methyl (3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate

DMP (6.77 g, 15.2 mmol) was added in portions to a 0° C. solution ofmethyl (3S)-3-[[(benzyloxy)carbonyl]amino]-4-hydroxybutanoate (3.00 g,10.1 mmol) in DCM (40 mL). The mixture was stirred for 2 h at 25° C. Thereaction was quenched with saturated aqueous sodium thiosulfate (10 mL).The solids were filtered out and the filter cake was washed with DCM(3×10 mL). The filtrate was washed with sodium bicarbonate (2×20 mL,sat.). The combined organic layers were dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by reverse phase chromatography(Column, C18 silica gel; Mobile phase, A: water (containing 10 mMNH₄HCO₃) and B: ACN (5% to 50% in 5 min); Detector, UV 254/220 nm) toafford methyl (3S)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate asyellow oil (2.00 g). LCMS (ES, m/z) 266 [M+H]⁺.

Step 6. BenzylN-[(3S)-5-oxo-1-[(1r,3r)-3-[[(tert-butoxy)carbonyl]amino]cyclobutyl]pyrrolidin-3-yl]carbamate

A solution of tert-butyl N-[(trans)-3-aminocyclobutyl]carbamate (545 mg,2.78 mmol) and methyl (35)-3-[[(benzyloxy)carbonyl]amino]-4-oxobutanoate(820 mg, 2.78 mmol) in DCM (30 mL) was stirred for 1 h at 25° C. Sodiumtriacetoxyborohydride (807 mg, 3.62 mmol) was added in two portions, andthe resulting mixture was stirred for additional 14 h at 25° C. Thereaction was quenched by the addition of water/ice (30 mL). Theresulting mixture was extracted with DCM (2×50 mL). The combined organiclayers were washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue was treatedwith DMF (5 mL). The solids were collected by filtration, washed withMeOH (3×10 mL) and dried in an oven to afford benzylN-[(3S)-5-oxo-1-[(trans)-3-[[(tert-butoxy)carbonyl]amino]cyclobutyl]pyrrolidin-3-yl]carbamateas a white solid (800 mg). LCMS (ES, m/z) 404 [M+H]⁺.

Step 7. tert-butylN-[(1r,3r)-3-(4-amino-2-oxopyrrolidin-1-yl)cyclobutyl]carbamate

A mixture of benzylN-[(3S)-5-oxo-1-[(1r,3r)-3-[[(tert-butoxy)carbonyl]amino]cyclobutyl]pyrrolidin-3-yl]carbamate(800 mg, 1.99 mmol) and palladium on carbon (500 mg, 10%) in methanol(30 mL) was stirred for 4 h at 25° C. under hydrogen atmosphere(balloon). The solids were filtered out and the filter cake was washedwith methanol (2×5 mL). The filtrate was concentrated under reducedpressure to afford tert-butylN-[(trans)-3-(4-amino-2-oxopyrrolidin-1-yl)cyclobutyl]carbamate ascolorless oil (480 mg). LCMS (ES, m/z) 270 [M+H]⁺.

Step 8. tert-butylN-[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]carbamate

A mixture of tert-butylN-[(trans)-3-(4-amino-2-oxopyrrolidin-1-yl)cyclobutyl]carbamate (300 mg,1.12 mmol), 2-bromo-5-cyclohexyl-1,3-thiazole (360 mg, 1.32 mmol),BrettPhos (120 mg, 0.220 mmol), 3^(rd) generation BrettPhos precatalyst(100 mg, 0.100 mmol), and t-BuOK (180 mg, 1.52 mmol) in dioxane (20 mL)was stirred for 1 h at 100° C. After cooling to 25° C., the reaction wasquenched by the addition of water (30 mL). The resulting mixture wasextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by reverse phasechromatography (Column, C18 silica gel; Mobile phase, A: water(containing 10 mM NH₄HCO₃) and B: ACN (30% to 70% in 10 min); Detector,UV 254/220 nm) to afford tert-butylN-[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]carbamateas a yellow solid (300 mg). LCMS (ES, m/z) 435 [M+H]⁺.

Step 9.4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-1-[(trans)-3-aminocyclobutyl]pyrrolidin-2-one2,2,2-trifluroacetate

A solution of tert-butylN-[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]carbamate(180 mg, 0.331 mmol) and TFA (1 mL) in DCM (5 mL) was stirred for 1 h at25° C. The resulting mixture was concentrated under vacuum to afford4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-1-[(trans)-3-aminocyclobutyl]pyrrolidin-2-one2,2,2-trifluoroacetate as yellow oil (200 mg). LCMS (ES, m/z) 335[M+H]⁺.

Step 10.[[(trans)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]amino]formonitrile

A mixture of4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-1-[(trans)-3-aminocyclobutyl]pyrrolidin-2-one2,2,2-trifluoroacetate (200 mg, 0.464 mmol) and NaHCO₃ (315 mg, 3.56mmol) in DMF (4 mL) was stirred for 30 min at 0° C. A solution ofcyanogen bromide (40.0 mg, 0.360 mmol) in DMF (1 mL) was added dropwiseat 0° C. The resulting mixture was stirred for 14 h at 25° C. Thereaction was quenched by the addition of water/ice (10 mL). Theresulting mixture was extracted with ethyl acetate (2×20 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD, 5μm, 19×150 mm; Mobile Phase, A: water (containing 10 mM ammoniumbicarbonate) and B: CH₃CN (2% to 40% over 1 min); Detector: UV 254/220nm). The product fractions were lyophilized to afford[[(1r,3r)-3-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]amino]formonitrileas a white solid (70 mg). LCMS (ES, m/z) 360 [M+H]⁺.

Step 11.(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)aminol-2-oxopyrrolidin-1-yl]cyclobutyl]amino)formonitrile

[[(1r,3r)-3-[4-[(5-Cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]amino]formonitrile(70.0 mg, 0.175 mmol) was separated by Chiral-HPLC (Column: CHIRALPAKIE, 2×25 cm, 5 um; Mobile Phase A: MTBE (containing 0.2% IPA) and B:EtOH (hold 20% in 14 min); Flow rate. 17 mL/min; Detector: 220/254 nm;RT₁: 9.148 min; RT₂:11.792 min). The first eluting isomer (RT₁=9.148min) was collected and lyophilized to afford a yellow oil arbitrarilyassigned as{[(1r,3r)-3-[(4S)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]amino}formonitrile(28.3 mg). ¹H-NMR (DMSO-46, 400 MHz) δ (ppm): 7.68 (br s, 1H), 7.24 (brs, 1H), 6.72 (s, 1H), 4.73-4.69 (m, 1H), 4.26-4.24 (m, 1H), 3.80-3.72(m, 2H), 3.26-3.21 (m, 1H), 2.71-2.59 (m, 2H), 2.51-2.46 (m, 1H),2.25-2.20 (m, 1H), 2.11-2.06 (m, 2H), 1.89-1.87 (m, 2H), 1.74-1.71 (m,2H), 1.66-1.63 (m, 1H), 1.37-1.13 (m, 6H). LCMS (ES, m/z) 360 [M+H]⁺.The second eluting isomer (RT=11.792 min) was collected and lyophilizedto afford a yellow oil arbitrarily assigned as{[(1r,3r)-3-[(4R)-4-[(5-cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1-yl]cyclobutyl]amino}formonitrile(26.2 mg). LCMS (ES, m/z) 360 [M+H]⁺.

Example 7.{[(2r,4s)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino}carbonitrile(Compound 7-1)

Step 1. tert-butyl N-[5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate

Di-tert-butyl dicarbonate (0.600 mL, 2.73 mmol) was added to a solutionof 2-amino-6-azaspiro[3.4]octan-5-one (300 mg, 2.14 mmol) and Na₂CO₃(454 mg, 4.24 mmol) in dioxane (5 mL) and water (0.5 mL) and thesolution stirred for 4 h at 25° C. The resulting mixture was dilutedwith water (10 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified byreverse phase chromatography (Column, C18 silica gel; Mobile phase, A:water (containing 10 mM NH4HCO3) and B: ACN (5% to 50% in 5 min);Detector, UV 254/220 nm) to afford tert-butylN-[5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate as a white solid (400 mg).LCMS (ES, m/z) 241 [M+H]⁺.

Step 2. tert-butylN-[6-(5-tert-butyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate

A mixture of tert-butyl N-[5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate(654 mg, 2.59 mmol), 2-bromo-5-tert-butyl-1,3-thiazole (600 mg, 2.59mmol), K₃PO₄ (1.67 g, 7.79 mmol), CuI (99.6 mg, 0.518 mmol), andmethyl[2-(methylamino)ethyl]amine (115 mg, 1.30 mmol) in toluene (12 mL)was stirred for 16 h at 100° C. After cooling to 25° C., the reactionwas quenched by the addition of water (50 mL). The resulting mixture wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous sodium sulfate.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography (eluting with 3:7petroleum ether/ethyl acetate) to affordN-[6-(5-tert-butyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carbamateas a yellow solid (690 mg). LCMS (ES, m/z): 380 [M+H]⁺.

Step 3. tert-butylN-[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate

A solution of tert-butylN-[6-(5-tert-butyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate(600 mg, 1.50 mmol) and NCS (300 mg, 2.25 mmol) in acetonitrile (10 mL)was stirred for 16 h at 60° C. The mixture was allowed to cool down to25° C. The reaction was quenched by the addition of water (20 mL). Theresulting mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel chromatography (eluting with 1:1petroleum ether/ethyl acetate) to afford tert-butylN-[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carbamateas yellow oil (270 mg). LCMS (ES, m/z): 414, 416 [M+H]⁺.

Step 4.2-amino-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-6-azaspiro[3.4]octan-5-one2,2,2-trifluoroacetate

A solution of tert-butylN-[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]carbamate(200 mg, 0.460 mmol) and TFA (2 mL) in DCM (5 mL) was stirred for 1 h at25° C. The resulting mixture was concentrated under vacuum to afford2-amino-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-6-azaspiro[3.4]octan-5-one2,2,2-trifluroracetate as yellow oil (210 mg). LCMS (ES, m/z): 314, 316[M+H]⁺.

Step 5.[[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrile

A mixture of2-amino-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-6-azaspiro[3.4]octan-5-one2,2,2-trifluroracetate (150 mg, 0.365 mmol), NaHCO₃ (132 mg, 1.58 mmol)and BrCN (33.4 mg, 0.320 mmol) in DMF (3 mL) was stirred for 4 h at 25°C. The reaction was quenched by the addition of water (10 mL). Theresulting mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC (Column: XBridge Prep Phenyl OBD Column, 5 μm, 19×150 mm;Mobile Phase, A: water (containing 0.05% ammonium bicarbonate) and B:CH₃CN (13% to 37% in 7 min); Detector: UV 254 nm). The product fractionswere lyophilized to afford[[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrileas a white solid (70.0 mg). LCMS (ES, m/z): 314, 316 [M+H]⁺.

Step 6.[[(2s,4r)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrileand[[(2r,4s)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrile

[[6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrile(70.0 mg, 0.223 mmol) was separated by Chiral-HPLC (Column, CHIRALPAKIA, 5 um, 2×25 cm; Mobile phase, A: hexane and B: ethanol (hold 30% in10 min); flow rate: 20 mL/min; Detector: 254 and 220 nm; RT₁: 7.043 min;RT₂: 8.368 min). The product fraction (RT: 7.043 min) was lyophilized toafford a white solid arbitrarily assigned as[[(2s,4r)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrile(22.6 mg). ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 7.35 (br s, 1H), 3.89-3.86(m, 2H), 3.83-3.82 (m, 1H), 2.34-2.23 (m, 6H), 1.41 (s, 9H). LCMS (ES,m/z): 339, 341[M+H]⁺.

The product fraction (RT: 8.368 min) was lyophilized to afford a whitesolid arbitrarily assigned as[[(2r,4s)-6-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2-yl]amino]formonitrile(15.1 mg). ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 7.30 (br s, 1H), 3.88-3.85(m, 2H), 3.81-3.80 (m, 1H), 2.63-2.62 (m, 2H), 2.28-2.24 (m, 2H),2.16-2.12 (m, 2H), 1.42 (s, 9H). LCMS (ES, m/z): 339, 341[M+H]⁺.

The following compounds were synthesized according to Example 7:

Example MS m/z No. Structure Chemical Name [M + H]+ 1H NMR Compound 7-2

{[(2s,4r)-6-(4-chloro- 5-cyclohexyl-1,3- thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan- 2- yl]amino}carbonitrile 365, 367 7.35 (br s, 1H),3.92-3.88 (m, 2H), 3.83-3.79 (m, 1H), 2.86-2.85 (m, 1H), 2.32-2.24 (m,6H), 1.90-1.87 (m, 2H, 1.79-1.76 (m, 2H), 1.70-1.67 (m, 1H), 1.38-1.18(m, 5H) Compound 7-3

{[(2r,4s)-6-(4-chloro- 5-cyclohexyl-1,3- thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan- 2- yl]amino}carbonitrile 365, 367 7.28 (br s, 1H),3.90-3.87 (m, 2H), 3.84-3.78 (m, 1H), 2.86-2.85 (m, 1H), 2.66-2.61 (m,2H), 2.28-2.25 (m, 2H), 2.15-2.08 (m, 2H), 1.90-1.87 (m, 2H), 1.79-1.76(m, 2H), 1.70-1.67 (m, 1H), 1.41-1.18 (m, 5H)

Example 8.N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-methoxycyclobutane-1-carboxamide(Compound 8-1)

Step 1. 5-tert-butyl-1,3-thiazol-2-amine

A solution of 3,3-dimethylbutanal (20.0 g, 0.200 mol), pyrrolidine (17.5mL, 0.214 mol) and TsOH (40.0 mg, 0.232 mol) in cyclohexane (280 mL) washeated to reflux for 3 h. After cooling to 25° C., the solvent wasremoved under reduced pressure. The residue was dissolved in methanol(80 mL). The resulting solution was added into a stirring mixture ofsulfur (6.40 g, 194 mmol) and cyanamide (8.39 g, 0.200 mol) in methanol(20 mL) at 0° C. The reaction mixture was stirred for 12 h at 25° C. andthen concentrated under reduce pressure. The residue was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford 5-tert-butyl-1,3-thiazol-2-amine as a light yellowsolid (8.10 g). LCMS (ES, m/z): 157 [M+H]⁺.

Step 2. tert-butyl N-(5-tert-butyl-1,3-thiazol-2-yl)carbamate

A solution of 5-tert-butyl-1,3-thiazol-2-amine (500 mg, 3.21 mmol),di-tert-butyl dicarbonate (1.39 g, 6.38 mmol), and Na₂CO₃ (680 mg, 6.42mmol) in ethyl acetate (10 mL) and water (10 mL) was stirred for 16 h at25° C. The reaction solution was diluted with water (30 mL). Theresulting mixture was extracted with ethyl acetate (3×60 mL). Thecombined organic layers were washed with brine (70 mL), dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography (eluting with 1:4ethyl acetate/petroleum ether) to afford tert-butylN-(5-tert-butyl-1,3-thiazol-2-yl)carbamate as a yellow solid (700 mg).LCMS (ES, m/z): 257 [M+H]⁺.

Step 3. tert-butyl N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)carbamate

A solution of tert-butyl N-(5-tert-butyl-1,3-thiazol-2-yl)carbamate (700mg, 2.73 mmol) and NCS (852 mg, 3.55 mmol) in MeCN was stirred for 2 hat 60° C. After cooling down to 25° C., the solids were filtered out andthe filtrate was concentrated under reduced pressure. The residue wasdiluted with water (50 mL) at 25° C. The resulting mixture was extractedwith ethyl acetate (2×50 mL). The organic layers were combined, washedwith brine (40 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 1:5 ethyl acetate/petroleum ether) toafford tert-butyl N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)carbamate asa white solid (530 mg). LCMS (ES, m/z): 291, 293 [M+H]⁺.

Step 4. 5-tert-butyl-4-chloro-1,3-thiazol-2-amine

A solution of tert-butylN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)carbamate (525 mg, 1.80 mmol)and TFA (2 mL) in DCM (5 mL) was stirred for 14 h at 25° C. Theresulting mixture was concentrated under vacuum. The residue waspurified by reverse phase chromatography (Column, C18 silica gel; Mobilephase, A: water (containing 10 Mm NH₄HCO₃) and B: ACN (10% to 50% in 8min); Detector, UV 254/220 nm) to afford5-tert-butyl-4-chloro-1,3-thiazol-2-amine as a yellow solid (310 mg).LCMS (ES, m/z): 191, 193 [M+H]⁺.

Step 5.2-(3-Hydroxycyclobutyl)-2,3,3a,7a-tetrahydro-1H-isoindole-1,3-dione

Triethylamine (20.2 mL, 192 mmol) was added to a solution of3-aminocyclobutan-1-ol hydrochloride (10.0 g, 76.8 mmol) and1,3-dihydro-2-benzofuran-1,3-dione (15.5 g, 100 mmol) in toluene (400mL). The resulting mixture was stirred for 6 h at 120° C. After coolingto 25° C., the resulting mixture was concentrated under reducedpressure. The residue was purified by silica gel chromatography (elutingwith 1:1 ethyl acetate/petroleum ether) to afford2-(3-hydroxycyclobutyl)-2,3,3a,7a-tetrahydro-1H-isoindole-1,3-dione as awhite solid (8.00 g). LCMS (ES, m/z): 218 [M+H]⁺.

Step 6. 2-(3-Oxocyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione

DMP (7.91 g, 18.6 mmol) was added in portions to a 0° C. solution of2-(3-hydroxycyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione (3.00 g, 12.4mmol) in DCM (60 mL). The resulting mixture was stirred for 2 h at 25°C. The solids were filtered out and the filter cake was washed with DCM(3×20 mL). The filtrate was concentrated under reduced pressure. Theresidue was treated with ethyl acetate (20 mL). The solids werecollected by filtration and dried in an oven to give2-(3-oxocyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione as a white solid(2.70 g). LCMS (ES, m/z): 216 [M+H]⁺.

Step 7.3-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carbonitrile

ZnI₂ (210 mg, 0.630 mmol) was added to a 0° C. solution of2-(3-oxocyclobutyl)-2,3-dihydro-1H-isoindole-1,3-dione (7.50 g, 31.4mmol) and TMSCN (200 mL). The resulting mixture was stirred for 20 h at25° C., and then concentrated under vacuum. The residue was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carbonitrileas a white solid (5.50 g). LCMS (ES, m/z): 315 [M+H]⁺.

Step 8. Methyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxylate

H₂SO₄ (25.0 mL, con.) was added to a 0° C. solution of3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-[(trimethylsilyl)oxy]cyclobutane-1-carbonitrile(6.00 g, 17.2 mmol) in MeOH (100 mL). The reaction mixture stirred for 3h at 90° C. After cooling to 25° C., the solvent was removed undervacuum. The pH value of the residue was adjusted to 7-8 with saturatedaqueous Na₂CO₃ solution. The resulting mixture was extracted with DCM(2×100 mL). The combined organic layers were dried over anhydrous sodiumsulfate. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by reverse phase chromatography(Column, C18 silica gel; Mobile phase, A: water (containing 0.05% TFA)and B: ACN (10% to 50% in 10 min); Detector, UV 254/220 nm) to affordmethyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxylate(2.10 g) as a yellow solid. LCMS (ES, m/z): 276 [M+H]⁺.

Step 9. Methyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxylate

A mixture of methyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxylate(500 mg, 1.64 mmol), CH₃I (0.540 mL, 8.21 mmol) and Ag₂O (4.00 g, 16.4mmol) in DCM (8 mL) was stirred for 20 h at 40° C. The solids werefiltered out and the filter cake was washed with DCM (2×10 mL). Thefiltrate was concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (Column, C18 silica gel; Mobilephase, A: water (containing 0.05% TFA) and B: ACN (40% to 80% in 10min); Detector, UV 254/220 nm) to afford methyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxylate(200 mg) as a white solid. LCMS (ES, m/z): 290 [M+H]⁺.

Step 10.3-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxylicacid

A mixture of methyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxylate(400 mg, 1.38 mmol) and hydrochloric acid (8 mL, 4N) was stirred for 4 hat 90° C. After cooling to 25° C., the resulting mixture wasconcentrated under reduced pressure. The residue was purified by reversephase chromatography (Column, C18 silica gel; Mobile Phase, A: water(containing 0.05% TFA) and B: CH₃CN (18% to 25% over 8 min); Detector:UV 220/254 nm) to afford3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxylicacid as a white solid (200 mg). LCMS (ES, m/z): 276 [M+H]⁺.

Step 11.N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxamide

A mixture of3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxylicacid (290 mg, 0.948 mmol), 5-tert-butyl-4-chloro-1,3-thiazol-2-amine(301 mg, 1.42 mmol), DCC (515 mg, 2.37 mmol) and DMAP (305 mg, 2.37mmol) in DCM (10 mL) was stirred for 30 h at 25° C. The solids werefiltered out and the filtrate was diluted with water (40 mL). Theresulting mixture was extracted with DCM (2×40 mL). The combined organiclayers were dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (eluting with 1:1 ethyl acetate/petroleum ether) toaffordN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxamideas a yellow solid (150 mg). LCMS (ES, m/z): 448, 450 [M+H]⁺.

Step 12.3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-methoxycyclobutane-1-carboxamide2,2,2-trifluoroacetate

A solution ofN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-methoxycyclobutane-1-carboxamide(140 mg, 0.281 mmol) and hydrazine hydrate solution (0.140 mL, 80% inwater) in EtOH (4 mL) stirred for 4 h at 50° C. After cooling to 25° C.,the resulting mixture was concentrated under vacuum. The residue waspurified by reverse phase chromatography (Column, C18 silica gel; Mobilephase, A: water (containing 0.05% TFA) and B: ACN (10/% to 50% in 10min); Detector, UV 254/220 nm) to afford3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-methoxycyclobutane-1-carboxamide2,2,2-trifluoroacetate as a yellow solid (70.0 mg). LCMS (ES, m/z): 318,320 [M+H]⁺.

Step 13.N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-methoxycyclobutane-1-carboxamide

A mixture of3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-methoxycyclobutane-1-carboxamide2,2,2-trifluoroacetate (70.0 mg, 0.220 mmol), NaHCO₃ (185 mg, 2.20 mmol)and BrCN (23.3 mg, 0.220 mmol) in DMF (2 mL) was stirred for 2 h at 25°C. The reaction was quenched by the addition of water/ice (5 mL). Theresulting mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (5 mL), dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified byPrep-HPLC (Column: XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm;Mobile Phase, A: water (containing 10 mM ammonium bicarbonate) and B:acetonitrile (65% to 75% in 7 min); Detector: UV 254 nm). The productfractions were lyophilized to affordN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-methoxycyclobutane-1-carboxamideas a white solid (27.3 mg). ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 10.28 (brs, 1H), 7.30 (br s, 1H), 3.10 (s, 3H), 2.77-2.76 (m, 2H), 2.51-2.50 (m,2H), 1.41 (s, 9H). LCMS (ES, m/z): 343, 345 [M+H]⁺.

Example 9.(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide(Compound 9-1) and(1r,3r)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide(Compound 9-2)

Step 1. Methyl1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxylate

A solution of methyl3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-1-hydroxycyclobutane-1-carboxylate(1.50 g, 4.90 mmol), DMF (3 mL) and SOCl₂ (30 mL) in CCl₄ (30 mL) wasstirred for 30 h at 100° C. After cooling to 25° C., the resultingmixture was concentrated under reduced pressure. The residue waspurified by reverse phase chromatography (Column, C18 silica gel; Mobilephase, A: water (0.05% TFA) and B: ACN (10% to 50% in 10 min); Detector,UV 254/220 nm) to afford methyl1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxylateas a white solid (500 mg). LCMS (ES, m/z): 294, 296 [M+H]⁺.

Step 2.1-Chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxylicacid

A mixture of methyl1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxylate(500 mg, 1.70 mmol) and hydrochloric acid (3 mL, 4 N) was stirred for 1h at 90° C. After cooling down to 25° C., the resulting mixture wasconcentrated under vacuum. The residue was purified by reverse phasechromatography (Column, C18 silica gel; Mobile phase, A: water(containing 0.05% TFA) B: ACN (10% to 80% in 10 min); Detector, UV254/220 nm) to afford1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxylicacid as a white solid (360 mg). LCMS (ES, m/z): 280, 282 [M+H]⁺.

Step 3.N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxamide

A solution of1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxylicacid (360 mg, 1.28 mmol) and 5-tert-butyl-4-chloro-1,3-thiazol-2-amine(294 mg, 1.39 mmol) in pyridine (10 mL) was stirred for 5 min at 0° C.POCl₃ (0.46 mL, 9.23 mmol) was added at 0° C., and the resulting mixturestirred for an additional 14 h at 0° C. The reaction was then quenchedby the addition of ice/water (20 mL). The resulting mixture wasextracted with ethyl acetate (2×40 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated undervacuum. The residue was purified by silica gel chromatography (elutingwith 1:1 ethyl acetate/petroleum ether) to affordN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxamideas a yellow solid (280 mg). LCMS (ES, m/z): 452, 454 [M+H]⁺.

Step 4.3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chlorocyclobutane-1-carboxamide2,2,2-trifluoroacetate

A solution ofN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclobutane-1-carboxamide(280 mg, 0.619 mmol) and hydrazine hydrate solution (0.29 mL, 80% inwater) in EtOH (5 mL) was stirred for 2 h at 50° C. After cooling downto 25° C., the resulting mixture was concentrated under vacuum. Theresidue was purified by reverse phase chromatography (Column, C18 silicagel; Mobile phase, A: water (containing 0.05% TFA) and B: ACN (10% to50% in 10 min); Detector, UV 254/220 nm) to afford3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chlorocyclobutane-1-carboxamide2,2,2-trifluoroacetate as a white solid (100 mg). LCMS (ES, m/z): 322,324 [M+H]⁺.

Step 5.N-(5-tert-butyl-4-chloro-,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide

Sodium bicarbonate (182 mg, 2.06 mmol) was added into a stirringsolution of3-amino-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chlorocyclobutane-1-carboxamide2,2,2-trifluoroacetate (100 mg, 0.228 mmol) in DMF (3 mL). The resultingsolution was stirred for 0.5 h at 25° C. A solution of BrCN (23.0 mg,0.206 mmol) in DMF (0.5 mL) was added at 0° C., and the resultingsolution stirred for 14 h at 25° C. The reaction was then quenched bythe addition of ice/water (10 mL). The resulting mixture was extractedwith ethyl acetate (2×20 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBDColumn, 5 μm, 19×150 mm; Mobile Phase, A: water (containing 10 mMammonium bicarbonate) and B: CH₃CN (45% to 75% over 7 min); Detector: UV254 nm). The product fractions were lyophilized to affordN-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamideas a white solid (30.0 mg). LCMS (ES, m/z): 347, 349 [M+H]⁺.

Step 6.(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide

N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide(30.0 mg, 0.086 mmol) was separated by Chiral-HPLC (Column: CHIRALPAKIG, 2×25 cm, 5 um; Mobile Phase A: n-hexane and B: EtOH (hold 10% in 30min); Flow rate: 20 mL/min; Detector: 220 and 254 nm; RT1:18.708 min;RT2:21.346 min). The first product fractions (RT=18.708 min) werelyophilized to afford a white solid arbitrarily assigned as(1s,3s)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide(1.40 mg). ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 12.78 (br s, 1H), 7.50 (brs, 1H), 3.48-3.38 (m, 1H), 2.60-2.52 (m, 4H), 1.42 (s, 9H). LCMS (ES,m/z): 347,349 [M+H]⁺. The second product fractions (RT=21.346 min) werelyophilized to afford a white solid arbitrarily assigned as(1r,3r)-N-(5-tert-butyl-4-chloro-1,3-thiazol-2-yl)-1-chloro-3-(cyanoamino)cyclobutane-1-carboxamide(25.0 mg). ¹H-NMR (DMSO-dr, 400 MHz) δ (ppm): 12.77 (br s, 1H), 7.31 (brs, 1H), 4.04-3.99 (m, 1H), 2.85-2.75 (m, 4H), 1.42 (s, 9H). LCMS (ES,m/z): 347, 349 [M+H]⁺.

Example 10-1.cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide(Compound 10-1)

Step 1. cis-tert-butylN-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclohexyl]carbamate

Into a 25 mL round-bottom flask was placedcis-4-[(tert-butoxy)carbonyl]aminocyclohexane-1-carboxylic acid (160 mg,0.66 mmol), N,N-dimethylformamide (5 mL), N,N-diisopropylethylamine (212mg, 1.64 mmol), HATU (417 mg, 1.10 mmol) and 5-cyclohexylthiazol-2-amine(100 mg, 0.49 mmol). The resulting solution was stirred for 18 h at 25°C. The resulting solution was poured into water (10 mL) and thenextracted with ethyl acetate (3×10 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gel chromatography(eluting with 1:1 ethyl acetate/petroleum ether) to affordcis-tert-butylN-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclohexyl]carbamate as ayellow oil. LC-MS (ESI) m/z 408.2 [M+H]⁺

Step 2.cis-4-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamideTFA salt

Into a 25 mL round-bottom flask was placed cis-tert-butylN-[4-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclohexyl]carbamate (70mg, 0.15 mmol), dichloromethane (4 mL) and trifluoroacetic acid (1 mL).The resulting solution was stirred for 2 h at 25° C. The reactionmixture was concentrated under vacuum. The residue was treated withethyl ether and dried under vacuum to affordcis-4-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamideTFA salt as a yellow oil. LC-MS (ESI) m/z 308.2 [M+H]⁺

Step 3.cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide

Into a 25 mL round-bottom flask was placedcis-4-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamideTFA salt (40 mg, 0.12 mmol), tetrahydrofuran (5 mL) and triethylamine(26 mg, 0.26 mmol). Then cyanogen bromide (13 mg, 0.12 mmol) was addedat −20° C. The resulting solution was stirred for 1 h at −20° C. Thereaction mixture was poured into water (5 mL) and then extracted withethyl acetate (3×5 mL). The residue was purified by prep-TLC (elutingwith 10:1 dichloromethane/methanol), and further purified by prep-HPLC(Column: XBridge Shield RP18 OBD Column, 130 Å, 5 μm, 19 mm×150 mm;Mobile phase: water (10 mM NH₄HCO₃), MeCN (40% MeCN up to 65% over 7min); Flow rate: 20 mL/min; Detector: 254 & 220 nm) to affordcis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide.¹H NMR (300 MHz, DMSO-d₆) δ11.83 (br s, 1H), 7.14 (s, 1H), 6.77 (s, 1H),2.76-2.68 (m, 1H), 2.65-2.50 (m, 1H), 1.95-1.81 (m, 2H), 1.76-1.49 (m,11H), 1.43-1.31 (m, 4H), 1.29-1.22 (m, 2H). LC-MS (ESI) m/z 333.2 [M+H]⁺

The following compounds were prepared according to Example 10-1:

Compound 10-2.trans-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆), δ 11.85 (s, 1H), 7.14 (s, 1H), 6.86 (d,J=4.80 Hz, 1H), 3.00-2.91 (m, 1H), 2.75 (s, 1H), 2.44-2.36 (m, 1H),1.94-1.84 (m, 6H), 1.73-1.64 (m, 3H), 1.54-1.42 (m, 2H), 1.38-1.23 (m,7H).

LC-MS (ESI) m/z 333.2 [M+H]⁺

Compound 10-3.(1R,2R)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide

H NMR (300 MHz, DMSO-d₆) δ 7.15 (s, 1H), 3.77-3.70 (m, 1H), 2.90-2.76(m, 2H), 2.27-1.92 (m, 4H), 1.74-1.60 (m, 7H), 1.43-1.01 (m, 5H).

LC-MS (ESI) m/z 319.2 [M+H]⁺

Compound 10-4.(1R,3S)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.14 (d, J=0.60 Hz, 1H), 6.91(d, J=4.80 Hz, 1H), 2.98-2.97 (m, 1H), 2.76-2.53 (m, 1H), 2.50-2.49 (m,1H), 1.97-1.64 (m, 9H), 1.30-1.26 (m, 9H).

LC-MS (ESI) m/z 333.1 [M+H]⁺

Compound 10-5.(1S,3S)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.14 (d, J=0.60 Hz, 1H), 6.91(d, J=4.80 Hz, 1H), 2.98-2.97 (m, 1H), 2.76-2.53 (m, 1H), 2.50-2.49 (m,1H), 1.97-1.64 (m, 9H), 1.30-1.26 (m, 9H).

LC-MS (ESI) m/z 333.1 [M+H]⁺

Compound 10-6.(1S,3R)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆), δ 11.88 (s, 1H), 7.14 (s, 1H), 6.92 (d,J=4.80 Hz, 1H), 3.03-2.93 (m, 1H), 2.76-2.74 (m, 1H), 2.58-2.54 (m, 1H),2.01-1.64 (m, 9H), 1.42-1.39 (m, 9H).

LC-MS (ESI) m/z 333.1 [M+H]⁺

Compound 10-7.(1R,2S)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 7.09 (s, 1H), 3.75-3.62 (m, 1H), 2.95-2.70(m, 2H), 2.13-1.88 (m, 4H), 1.67-1.42 (m, 7H), 1.47-0.82 (m, 5H).

LC-MS (ESI) m/z 319.2 [M+H]⁺

Compound 10-8.(1S,2R)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 7.09 (s, 1H), 3.72-3.68 (m, 1H), 2.87-2.78(m, 2H), 2.00-1.80 (m, 4H), 1.68-1.39 (m, 7H), 1.36-0.96 (m, 5H).

LC-MS (ESI) m/z 319.2 [M+H]⁺

Compound 10-9.(1S,2S)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆) δ 7.16 (s, 1H), 3.78-3.70 (m, 1H), 2.90-2.73(m, 2H), 2.10-1.92 (m, 4H), 1.75-1.52 (m, 7H), 1.42-1.18 (m, 5H).

LC-MS (ESI) m/z 319.2 [M+H]⁺

Compound 10-10.(1S,3S)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆), δ 12.00 (s, 1H), 7.20 (s, 1H), 6.85 (s, 1H),3.92-3.89 (m, 2H), 3.88 (s, 1H), 3.73-3.39 (m, 2H), 3.15-3.03 (m, 2H),2.08-1.96 (m, 3H), 1.92-1.83 (m, 3H), 1.82-1.73 (m, 1H), 1.67-1.66 (m,3H).

LC-MS (ESI) m/z 321.2 [M+H]⁺

Compound 10-11.(1R,3R)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1-carboxamide

¹H NMR (300 MHz, DMSO-d₆), δ 11.99 (s, 1H), 7.19 (s, 1H), 6.86 (s, 1H),3.92-3.87 (m, 2H), 3.72 (s, 1H), 3.46-3.39 (m, 2H), 3.13-3.03 (m, 2H),2.08-1.97 (m, 2H), 1.88-1.82 (m, 4H), 1.77-1.55 (m, 4H).

LC-MS (ESI) m/z 321.2 [M+H]⁺

Example 11-1.trans-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamide(Compound 11-1)

Step 1. tert-butylN-[(trans)-2-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclopropyl]carbamate

Into a 8 mL vial was placed(trans)-2-[(tert-butoxy)carbonyl]aminocyclopropane-1-carboxylic acid(132 mg, 0.62 mmol), N,N-dimethylformamide (1 mL),N,N-diisopropylethylamine (212 mg, 1.64 mmol), HATU (417 mg, 1.10 mmol)and 5-cyclohexyl-1,3-thiazol-2-amine (100 mg, 0.55 mmol). The resultingsolution was stirred for 2 h at 25° C. The reaction mixture was pouredinto water (2 mL) and then extracted with ethyl acetate (3×2 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified bysilica gel chromatography (eluting with 1:1 ethyl acetate/petroleumether) to afford tert-butylN-[(trans)-2-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclopropyl]carbamateas a white solid. LC-MS (ESI) m/z 366.1 [M+H]⁺

Step 2.(trans)-2-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamideHCl Salt

Into a 8 mL vial was placed tert-butylN-[(trans)-2-[(5-cyclohexyl-1,3-thiazol-2-yl)carbamoyl]cyclopropyl]carbamate(100 mg, 0.25 mmol), dichloromethane (2.4 mL) and a solution of HCl in1,4-dioxane (4 M, 0.9 mL). The resulting solution was stirred for 6 h at0° C. The resulting mixture was concentrated under vacuum, washed withethyl ether, filtered and concentrated under vacuum to afford(trans)-2-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamideHCl salt as a white solid. LC-MS (ESI) m/z 266.1 [M+H]⁺

Step 3.trans-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamide

Into a 8 mL vial was placed(trans)-2-amino-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamideHCl salt (70 mg, 0.21 mmol), N,N-dimethylformamide (1 mL) and sodiumbicarbonate (35 mg, 0.42 mmol). After cooling to 0° C., cyanogen bromide(22 mg, 0.21 mmol) was added. The resulting solution was stirred for 1 hat 0° C. and 18 h at room temperature. The reaction mixture was pouredinto water (2 mL) and then extracted with ethyl acetate (3×2 mL). Theorganic layers were combined, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The residue was purified byprep-TLC (eluting with 1:1 ethyl acetate/petroleum ether), and furtherpurified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 130 Å, 5μm, 19 mm×150 mm; Mobile phase: water (10 mM NH₄HCO₃), MeCN (35% MeCN upto 65% over 7 min); Flow rate: 20 mL/min; Detector: 254 & 220 nm). Thisresulted in(trans)-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamideas a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.15 (s, 1H), 7.29 (s,1H), 5.67-5.64 (m, 1H), 2.82-2.71 (m, 2H), 2.68-2.53 (m, 2H), 2.16-2.06(m, 1H), 1.97-1.92 (m, 2H), 1.77-1.75 (m, 2H), 1.69-1.66 (m, 1H),1.47-1.33 (m, 4H), 1.32-1.24 (m, 1H). LC-MS (ESI) m/z 291.2[M+H]⁺

The following compounds were prepared according to Example 11-1:

Compound 11-2.cis-2-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclopropane-1-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (br s, 1H), 7.29 (s, 1H), 5.67-5.64 (m,1H), 2.83-2.80 (m, 2H), 2.68-2.53 (m, 2H), 2.13-2.06 (m, 1H), 1.97-1.90(m, 2H), 1.77-1.74 (m, 2H), 1.69-1.61 (m, 1H), 1.47-1.33 (m, 4H),1.27-1.24 (m, 1H).

LC-MS (ESI) m/z 291.2[M+H]⁺

The following compounds were also prepared according to previous Example2-1 above:

Compound 2-2.(3S)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (br s, 1H), 7.13 (s, 1H), 7.01 (s,1H), 3.92-3.89 (m, 1H), 3.51-3.39 (m, 4H), 2.72-2.70 (m, 1H), 2.08-2.06(m, 1H), 1.95-1.92 (m, 3H), 1.74-1.72 (m, 3H), 1.34-1.31 ((m, 4H),1.26-1.16 (m, 1H).

LC-MS (ESI) m/z 320.4 [M+H]⁺

Compound 2-3.(3R)-3-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (br s, 1H), 7.13 (s, 1H), 7.01 (s,1H), 3.89 (s, 1H), 3.51-3.39 (m, 4H), 2.72-2.70 (m, 1H), 2.09-2.07 (m,1H), 1.99-1.92 (m, 3H), 1.74-1.66 (m, 3H), 1.34-1.31 (m, 4H), 1.26-1.16(m, 1H).

LC-MS (ESI) m/z 320.1 [M+H]⁺

Example 12-1.(1R,3S)-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide(Compound 12-1)

A half-dram vial was charged with(1R,3S)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylic acid(0.2 M in 1,4-dioxane, 225 μL, 45 μmol), 5-phenylthiazol-2-amine (0.2 Min 1,4-dioxane, 225 μL, 45 μmol) and DIEA (30 μL, neat, 172 μmol), thena solution of 2-chloro-1,3-dimethylimidazolinium chloride (0.2 M in DCE,275 μL, 55 μmol) was added. The vial was sealed and shaken at roomtemperature for 16 h. The reaction mixture was diluted with brine (500μL) and extracted with ethyl acetate (2×500 μL). The combined organiclayers were evaporated to dryness under a stream of N₂ and 1,4-dioxane(250 μL) was added to the residue. The vial was sealed and shaken at 50°C. for 15 min to dissolve the residue, then cooled to room temperature.HCl (4 M in 1,4-dioxane, 150 μL, 600 μmol) was added, the vial wassealed and shaken at room temperature for 3 h. The solvent wasevaporated and DMA (200 μL) and DIEA (50 μL, neat, 287 μmol) were added.The vial was sealed and shaken at 50° C. for 15 min to dissolve theresidue, then cooled to room temperature. Cyanogen bromide (0.4 M inDMA, 225 μL, 90 μmol) was added, the vial was sealed and shaken at roomtemperature for 3 h. DMSO (300 μL) and AcOH (45 μL) were added and themixture was purified by mass triggered preparative HPLC. Theproduct-containing fractions were combined and concentrated in a Genevacto afford(1R,3S)-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamideas an off-white solid. LC-MS (ESI) m/z 313 [M+H]⁺

The following compounds were synthesized according to Example 12-1:

Compound 12-2

(1S,3S)-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-3-yl)cyclopentane.-1-carboxamide LC-MS (ESI) m/z 296.2 [M + H]⁺ Compound 12-3

(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide LC-MS (ESI) m/z 319.2 [M + H]⁺ Compound12-4

(1S,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1-carboxamide LC-MS (ESI) m/z 313.2 [M + H]⁺ Compound 12-5

(1S,3S)-3-(cyanoamino)-N-(2,3- dihydro-1H-inden-5-yl)cyclopentane-1-carboxamide LC-MS (ESI) m/z 270.2 [M + H]⁺ Compound 12-6

(1S,3S)-3-(4-phenylpiperizine-1- carbonyl)cyclopentyl]amino}carbonitrileLC-MS (ESI) m/z 299.2 [M + H]⁺ Compound 12-7

(1S,3R)-N-(5-tcrt-butyl-1,3-thiazol-2- yl)-3-(cyanoamino)cyclopentane-1-carboxamide LC-MS (ESI) m/z 793.2 [M + H]⁺ Compound 12-8

{[(3S)-1-[2-(2,3-dichlorophenyl)-1,3- thiazole-4-carbonyl]pyrrolidin-3-yl]amino}carbonitrile LC-MS (ESI) m/z 367   [M + H]⁺ Compound 12-9

({1-[2-(2,4-dichlorophenyl)-1,3- thiazole-4-carbonyl]piperidin-4-yl}amino)carbonitrile LC-MS (ESI) m/z 381   [M + H]⁺

Example A: Biochemical Assay: Ubiquitin-Rhodamine 110 Assay for USP30Activity (USP30 Inhibitor Biochemical Assay)

In some embodiments, the compounds of the invention are USP30 inhibitorcompounds having an IC₅₀ value of 1 micromolar or less (e.g., between0.001 micromolar and 1 micromolar) as determined by the following USP30Inhibitor Biochemical Assay. In some embodiments, the compounds of theinvention are USP30 inhibitor compounds having an IC₅₀ value of lessthan 0.5 micromolar (e.g., between 0.001 micromolar and 0.5 micromolar)as determined by the following USP30 Inhibitor Biochemical Assay. Insome embodiments the compounds of the invention are preferably USP30inhibitor compounds having an IC₅₀ value of less than 0.1 micromolar(e.g., between 0.001 micromolar and 0.1 micromolar) as determined by thefollowing USP30 Inhibitor Biochemical Assay.

The assay was performed in a final volume of 9 μL in assay buffercontaining 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH 8.0 solution;Corning 46-031-CM)), 1 mM GSH (L-glutathione reduced, Sigma-Aldrich,G4251-100G), 0.03% BGG (0.22 μM filtered, Sigma, G7516-25G), and 0.01%Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of 10-point,3-fold serial dilution in DMSO were pre-dispensed into 1536 assay plates(Corning, #3724BC) for a final test concentration of 25 μM to 1.3 nM,top to lowest dose, respectively. Concentration and incubation timeswere optimized for the maximal signal-to-background while maintaininginitial velocity conditions at a fixed substrate concentration. Thefinal concentration of USP30 (human recombinant USP30, Boston Biochem,cat. #E-582) in the assay was 0.2 nM. Final substrate (Ub-Rh110;Ubiquitin-Rhodamine 110, UbiQ-126) concentration was 25 nM with[Ub-Rh110]<<Km. 3 μL of 2×USP30 was added to assay plates (pre-stampedwith compound), preincubated for 30 minutes and then treated with 3 μLof 2×Ub-Rh110. Plates were incubated for 30 minutes at room temperaturebefore addition of 3 μL of stop solution (final concentration of 10 mMcitric acid (Sigma, 251275-500G)). Fluorescence was read on the Envision(excitation at 485 nm and emission at 535 nm; Perkin Elmer) or on thePheraSTAR (excitation at 485 nm and emission at 535 nm; BMG Labtech).

For all assay formats data were reported as percent inhibition comparedwith control wells based on the following equation: %inh=1−((FLU−Ave_(Low))/(Ave_(High)−Ave_(Low))) where FLU=measuredFluorescence, Ave_(Low)=average Fluorescence of no enzyme control(n=16), and Ave_(High)=average Fluorescence of DMSO control (n=16). IC₅₀values were determined by curve fitting of the standard 4 parameterlogistic fitting algorithm included in the Activity Base softwarepackage: IDBS XE Designer Model205. Data is fitted using the LevenburgMarquardt algorithm.

The activity of compounds in the USP30 biochemical IC₅₀ assay (IC₅₀ranges) according to the present disclosure are reported in the tablesA1 to A3 below according to the following: “−”: inactive, “+”: 10-25 μM,“++”: 1-10 μM, “+++”: 0.1-1 μM, “++++”: <0.1 μM.

TABLE A1 Example USP30 No. Structure Chemical Name potency rangeCompound 1-1 

trans-3-(cyanoamino)-N-[5-(oxan-4-yl)- 1,3-thiazol-2-yl]cyclobutane-1-carboxamide ++ Compound 2-1 

3-(cyanoamino)-N-(5-cyclohexyl-1,3- thiazol-2-yl)azetidine-1-carboxamide++ Compound 3-1 

5-phenyl-N-[(trans)-3- cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide ++ Compound 4-1 

5-phenyl-N-[(cis)-3- (cyanoamino)cyclobutyl]-1,3-thiazole- 2-carboxamide++ Compound 5-1 

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide ++ Compound 5-2 

cis-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide + Compound 5-3 

cis-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide ++ Compound 5-4 

cis-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide ++ Compound 5-5 

trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-4-yl)cyclobutane-1-carboxamide ++ Compound 5-6 

trans-3-(cyanoamino)-N-(1-phenyl-1H- pyrazol-3-yl)cyclobutane-1-carboxamide ++ Compound 5-7 

trans-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclobutane-1-carboxamide +++ Compound 5-8 

trans-3-(cyanoamino)-N-(5-phenyl-1,3-thiazol-2-yl)cyclobutane-1-carboxamide ++ Compound 5-9 

cis-3-(cyanoamino)-N-(2,3-dihydro-1H-inden-5-yl)cyclobutane-1-carboxamide ++ Compound 5-10

cis-N-(5-tert-butyl-1,3-thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide + Compound 5-11

{[cis-3-(4-phenylpiperazine-1- carbonyl)cyclobutyl]amino}carbonitirile −Compound 5-12

trans-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclobutane-1-carboxamide ++ Compound 5-13

trans-N-(5-tert-butyl-1,3-thiazol-2-yl)- 3-(cyanoamino)cyclobutane-1-carboxamide +++ Compound 5-14

trans-3-(cyanoamino)-N-[4-(morpholin-4-yl)phenyl]cyclobutane-1-carboxamide +

TABLE A2 USP30 Example potentcy No. Structure Chemical Name rangeCompound 1-2

(1r,3r)-3-(cyanoamino)-N-(1- methyl-3-phenyl-1H-pyrazol-5-yl)cyclobutane-1-carboxamide +++ Compound 1-3

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)cyclobutane-1-carboxamide ++++ Compound 1-4

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-N-methylcyclobutane-1- carboxamide +++ Compound 1-5

(1r,3r)-N-(5-tert-butyl-1,3- thiazol-2-yl)-3-(cyanoamino)-N-methylcyclobutane-1- carboxamide +++ Compound 1-6

(1r,3r)-3-(cyanoamino)-N-(3- cyclohexyl-1-methyl-1H-pyrazol-5-yl)cyclobutane-1- carboxamide +++ Compound 1-7

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-4-methyl-1,3-thiazol-5-yl)cyclobutane-1- carboxamide +++ Compound 1-8

(1r,3r)-3-(cyanoamino)-N-{2- [2-(propan-2-yloxy)phenyl]-1,3-thiazol-5-yl}cyclobutane-1- carboxamide +++ Compound 1-9

(1r,3r)-3-(cyanoamino)-N-[2- (3,3-difluorocyclobutyl)-1,3-thiazol-5-yl]cyclobutane-1- carboxamide +++ Compound 1-10

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-11

(1r,3s)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-1-methylcyclobutane-1- carboxamide ++++ Compound 1-12

(1r,3r)-3-(cyanoamino)-N-{2- [(1S)-2,2-dimethylcyclohexyl]-1,3-thiazol-5-yl}cyclobutane-1- carboxamide ++++ Compound 1-13

(1r,3r)-3-(cyanoamino)-N-{2- [(1R)-2,2-dimethylcyclohexyl]-1,3-thiazol-5-yl}cyclobutane-1- carboxamide +++ Compound 1-14

(1r,3r)-N-(4-chloro-2- cyclohexyl-1,3-thiazol-5-yl)-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-15

(1R,3R)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-2,2-dimethylcyclobutane-1- carboxamide +++ Compound 1-16

(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(methoxymethyl)-1,3-thiazol-2- yl]cyclobutane-1-carboxamide ++++Compound 1-17

(1r,3r)-3-(cyanoamino)-N-(2- cyclohexyl-4-fluoro-1,3-thiazol-5-yl)cyclobutane-1- carboxamide +++ Compound 1-18

(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-19

(1r,3r)-N-(5-tert-butyl)-4- chloro-1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-20

(1r,3r)-N-[4-chloro-3- (trifluoromethyl)phenyl]-3-(cyanoamino)cyclobutane-1- carboxamide ++ Compound 1-21

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2R)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compound 1-22

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2S)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compond 1-23

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2S)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide ++++ Compound 1-24

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2R)-2-methylcyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide ++++ Compound 1-25

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-4-cyclopropyl-1,3-thiazol-2-yl)cyclobutane-1- carboxamide ++++ Compound 1-26

(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(1-cyclopropyl-1H-pyrazol-4-yl)-1,3-thiazol-2- yl]cyclobutane-1-carboxamide ++++Compound 1-27

(1r,3r)-3-(cyanoamino)-N-[4- (trifluoromethyl)pyridin-2-yl]cyclobutane-1-carboxamide +++ Compound 1-28

(1r,3r)-3-(cyanoamino)-N-{5- [(2S)-oxa-2-yl]-1,3-thiazol-2-yl}cyclobutane-1-carboxamide ++ Compound 1-29

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-4-methyl-1,3-thiazol-2-yl)cyclobutane-1- carboxamide ++++ Compound 1-30

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-1-methyl-1H-pyrazol-3-yl)cyclobutane-1- carboxamide +++ Compound 1-31

(1r,3r)-3-(cyanoamino)-N-[5- cyclohexyl-4-(trifluoromethyl)-1,3-thiazol-2-yl]cyclobutane-1- carboxamide ++++ Compound 1-32

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2R)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compound 1-33

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2S)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compound 1-34

(1r,3r)-3-(cyanoamino)-N-{5- [(1S,2S)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compound 1-35

(1r,3r)-3-(cyanoamino)-N-{5- [(1R,2R)-2- (trifluoromethyl)cyclohexyl]-1,3-thiazol-2-yl}cyclobutane-1- carboxamide +++ Compound 1-36

(1r,3r)-N-(4-chloro-5- cyclopropyl-1,3-thiazol-2-yl)-3-(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-37

(1r,3r)-N-{5-[(2R)- bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 1-38

(1r,3r)-N-{5-[(2S)- bicyclo[2.2.2]octan-2-yl]-1,3- thiazol-2-yl}-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-39

(1r,3r)-N-(5-chloro-1- cyclohexyl-1H-pyrazol-3-yl)-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-40

(1r,3r)-3-(cyanoamino)-N-[5- (3-cyanophenyl)-1,3-thiazol-2-yl]cyclobutane-1-carboxamide +++ Compound 1-41

(1r,3r)-N-[3-(3-chlorophenyl)- 1,2-oxazol-5-yl]-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-42

(1r,3s)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)-1-methylcyclobutane-1- carboxamide +++ Compound 1-43

(1r,3r)-N-[5-(3-chlorophenyl)- 1,2-oxazol-3-yl]-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-44

(1r,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-1-methylcyclobutane-1- carboxamide ++++ Compound 1-45

(1r,3r)-N-[3-(3-chlorophenyl)- 1,2-oxazol-5-yl]-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide +++ Compound 1-46

(1r,3s)-3-(cyanoamino)-N-(2- cyclohexyl-1,3-thiazol-5-yl)-1-ethylcyclobutane-1- carboxamide +++ Compound 1-47

(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-1-fluorocyclobutane-1- carboxamide +++ Compound 1-48

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-1-fluorocyclobutane-1- carboxamide ++++ Compound 1-49

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide ++++ Compound 1-50

(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide ++++ Compound 1-51

(1r,3r)-3-(cyanoamino)-N-[3- (3-cyanophenyl)-1,2-oxazol-4-yl]cyclobutane-1-carboxamide +++ Compound 1-52

(1r,3r)-N-[5-(3-chlorophenyl)- 1,2-oxazol-3-yl]-3- (cyanoamino)-N-methylcyclobutane-1- carboxamide +++ Compound 1-53

(1r,3r)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-oxazol-2-yl)cyclobutane-1-carboxamide +++ Compound 1-54

(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide ++++ Compound1-55

(1r,3r)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide ++++ Compound1-56

(1s,3s)-3-(cyanoamino)-1- fluoro-N-{3-[4- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}cyclobutane-1- carboxamide +++ Compound 1-57

(1r,3r)-3-(cyanoamino)-1- fluoro-N-{3-[4- (trifluoromethyl)phenyl]-1H-pyrazol-5-yl}cyclobutane-1- carboxamide +++ Compound 1-58

(1s,3s)-N-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-3-(cyanoamino)-1-fluoro-N- methylcyclobutane-1- carboxamide +++ Compound1-59

(1s,3s)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3- (cyanoamino)-1-fluorocyclobutane-1- carboxamide +++ Compound 1-60

(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3- (cyanoamino)-1-fluorocyclobutane-1- carboxamide ++++ Compound 1-61

(1r,3r)-3-(cyanoamino)-N-[3- (2-fluorophenyl)-5-methylphenyl]cyclobutane-1- carboxamide +++ Compound 1-62

(1r,3r)-N-(3-chloro-5- cyclohexylphenyl)-3- (cyanoamino)cyclobutane-1-carboxamide ++++ Compound 1-63

(1r,3r)-3-(cyanoamino)-N-[4- fluoro-3-(piperidin-1-yl)phenyl]cyclobutane-1- carboxamide +++ Compound 1-64

(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)cyclobutane-1- carboxamide +++ Compound 1-65

(1r,3r)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)-1-fluorocyclobutane-1- carboxamide ++++ Compound 1-66

(1s,3s)-3-(cyanoamino)-N-(7- cyclobutoxy-1,3-benzothiazol-2-yl)-1-fluorocyclobutane-1- carboxamide +++ Compound 1-67

(1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan- 2-yl]methyl}cyclobutane-1- carboxamide +++Compound 1-68

(1r,3r)-N-[4-(4-chlorophenyl)- 1,3-thiazol-2-yl]-3-(cyanoamino)cyclobutane-1- carboxamide +++ Compound 1-69

(1r,3r)-3-(cyanoamino)-N-(3- phenylphenyl)cyclobutane-1- carboxamide +++Compound 1-70

(1r,3r)-3-(cyanoamino)-N-{[4- (propan-2- yl)phenyl]methyl}cyclobutane-1-carboxamide ++++ Compound 1-71

(1r,3r)-3-(cyanoamino)-N- [(1s,4s)-4-tert- butylcyclohexyl]cyclobutane-1-carboxamide +++ Compound 1-72

(1r,3r)-3-(cyanoamino)-N- {[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan- 2-yl]methyl}cyclobutane-1- carboxamide +++Compound 1-73

(1r,3r)-3-(cyanoamino)-N-[3- (trifluoromethyl)phenyl]cyclobu-tane-1-carboxamide +++ Compound 3-2

{[1-(2-phenyl-1,3-thiazol-5- carbonyl)-1- azaspiro[3.3]heptan-6-yl]amino}carbonitrile +++ Compound 3-3

3-[4-(1-methyl-1H-pyrazol-4- yl)phenyl]-N-[(1s,3s)-3-(cyanoamino)cyclobutyl]-1,2- oxazol-5-carboxamide +++ Compound 3-4

{[(2r,4s)-5-{3-[4-(1-methyl- 1H-pyrazol-4-yl)phenyl]-1,2-oxazole-5-carbonyl}-5- azaspiro[3.4]octan-2- yl]amino}carbonitrile +++Compound 3-5

{[(4r,6s)-1-{3-[4-(1-methyl- 1H-pyrazol-4-yl)phenyl]-1,2-oxazole-5-carbonyl}-1- azaspiro[3.3]heptan-6- yl]amino}carbonitrile +++Compound 3-6

3-(3-cyanophenyl)-N-methyl- N-[(1r,3r)-3- (cyanoamino)cyclobutyl]-1,2-oxazole-5-carboxamide ++ Compound 6-1

{[(1r,3r)-3-[(4S)-4-[(5- cyclohexyl-1,3-thiazol-2-yl)amino]-2-oxopyrrolidin-1- yl]cyclobutyl]amino}carbonitrile +++Compound 7-1

{[(2r,4s)-6-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile ++++ Compound 7-2

{[(2s,4r)-6-(4-chloro- cyclohexyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile +++ Compound 7-3

{[(2r,4s)-6-(4-chloro-5- cyclohexyl-1,3-thiazol-2-yl)-5-oxo-6-azaspiro[3.4]octan-2- yl]amino}carbonitrile ++++ Compound 8-1

(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-3- (cyanoamino)-1-methoxycyclobutane-1- carboxamide ++++ Compound 9-1

(1s,3s)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-1- chloro-3-(cyanoamino)cyclobutane-1- carboxamide ++++ Compound 9-2

(1r,3r)-N-(5-tert-butyl-4- chloro-1,3-thiazol-2-yl)-1- chloro-3-(cyanoamino)cyclobutane-1- carboxamide +++

TABLE A3 USP30 Example potency no. Molecule Chemical Name range Compound10-1

cis-4-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1-carboxamide +++ Compound 10-2

trans-4-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol- 2-yl)cyclohexane-1-carboxamide ++ Compound 10-3

(1r,2R)-2-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane-1-carboxamide ++ Compound 10-4

(1R,3S)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane-1-carboxamide − Compound 10-5

(1S,3S)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane-1-carboxamide − Compound 10-6

(1S,3R)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane-1-carboxamide ++ Compund 10-7

(1R,2S)-2-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane-1-carboxamide ++ Compound 10-8

(1S,2R)-2-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane-1-carboxamide ++ Compound 10-9

(1S,2S)-2-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane-1-carboxamide ++ Compound 1-10

trans-3-(cyanoamino)-N- [5-(oxan-4-yl)-1,3-thiazol- 2-yl]cyclobutane-1-carboxamide ++ Compound 10-10

(1S,3S)-3-(cyanoamino)- N-[5-(oxan-4-yl)-1,3- thiazol-2-yl]cyclopentane-1-carboxamide ++ Compound 10-11

(1R,3R)-3-(cyanoamino)- N-[5-(oxan-4-yl)-1,3- thiazol-2-yl]cyclopentane-1-carboxamide + Compound 11-1

trans-2-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol- 2-yl)cyclopropane-1-carboxamide ++ Compound 11-2

cis-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclopropae-1-carboxamide ++ Compound 2-2

(3S)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol- 2-yl)pyrrolidine-1-carboxamide ++ Compound 2-3

(3R)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol- 2-yl)pyrrolidine-1-carboxamide Compound 12-1

(1R,3S)-3-(cyanoamino)- N-(5-phenyl-1,3-thiazol- 2-yl)cyclopentane-1-carboxamide ++ Compund 12-2

(1S,3S)-3-(cyanoamino)- N-(1-phenyl-1H-pyrazol- 3-yl)cyclopentane-1-carboxamide + Compound 12-3

(1S,3S)-3-(cyanoamino)- N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclopentane-1-carboxamide +++ Compound 12-4

(1S,3S)-3-(cyanoamino)- N-(5-phenyl-1,3-thiazol- 2-yl)cyclopentane-1-carboxamide ++ Compound 12-5

(1S,3S)-3-(cyanoamino)- N-(2,3-dihydro-1H-inden- 5-yl)cyclopentane-1-carboxamide + Compound 12-6

{[(1S,3S)-3-(4- phenylpiperazine-1- carbonyl)cyclopentyl]ami-no}carbonitrile − Compound 12-7

(1S,3R)-N-(5-tert-butyl- 1,3-thiazol-2-yl)-3- (cyanoamino)cyclopentane-1-carboxamide ++ Compound 12-8

{[(3S)-1-[2-(2,3- dichlorophenyl)-1,3- thiazole-4-carbonyl]pyrrolidin-3- yl]amino}carbonitrile ++ Compound 12-9

({1-[2-(2,4- dichlorophenyl)-1,3- thiazole-4- carobnyl]piperidin-4-yl}amino)carbonitrile +

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.Embodiments of the disclosure are set out in the following numberedclauses:

-   -   1. At least one chemical entity chosen from compounds of Formula        (I):

and pharmaceutically acceptable salts, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein:

R is independently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl groups,(C₁-C₆) alkoxy groups, (C₁-C₆) haloalkyl groups, (C₁-C₆) haloalkoxygroups, halogen, (C₃-C₆) cycloalkyl groups, and (C₃-C₆) heterocycloalkylgroups;

n is 0, 1, or 2;

wherein, if n is 2, the R groups can combine to form a fused ring systemwith R₁;

R₁ is chosen from 3-6 membered cyclic or heterocyclic groups;

R₂ is chosen from C(X)_(n), S(O)₂, N(X), heteroatom linkers, N(X)S(O)₂,N(X)S(O)₂N(X), carbonylalkyl groups, and carbonylheteroalkyl groups,wherein the alkyl portion of carbonylalkyl and carbonylheteroalkylgroups can optionally cyclize with R, R₁, or R₃:

X is independently chosen from hydrogen, alkyl groups, and heteroalkylgroups, wherein the alkyl and heteroalkyl groups can optionally cyclizewith R, R₁, or R₃ or with another X group when multiple X groups arepresent;

R₃ is chosen from hydrogen, halogens, alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, heteroalkoxy groups, haloalkoxy groups,carbonylalkyl groups, carbonylheteroalkyl groups, cyclic groups,heterocyclic groups, aryl groups, and heteroaryl groups, wherein anyrings are optionally substituted with 1 or 2 R groups;

R4 is independently chosen from alkyl groups, heteroalkyl groups,haloalkyl groups, alkoxy groups, cycloalkoxy groups, heteroalkoxygroups, haloalkoxy groups, carboxyalkyl groups, heterocarboxyalkylgroups, cyclic groups, heterocyclic groups, aryl groups and heteroarylgroups, wherein any rings are optionally substituted with 1 or 2 Ygroups;

Y is independently chosen from hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkylgroups, (C₁-C₆) heteroalkyl groups, (C₁-C₆) alkoxy groups, (C₁-C₆)haloalkyl groups, (C₁-C₆) haloalkoxy groups, halogen, (C₃-C₆) cycloalkylgroups, (C₃-C₆) heterocycloalkyl groups, (C₅-C₈) aryl groups, and(C₄-C₈) heteroaryl groups; and

m is 0, 1, or 2.

-   -   2. The chemical entity of clause 1, wherein R₁ is chosen from        cyclopropane, cyclobutane, cyclopentane, and cyclohexane.    -   3. The chemical entity of clause 1, wherein R₁ is chosen from        cyclobutane and cyclopentane.    -   4. The chemical entity of clause 1, wherein R₁ is chosen from        heterocyclic groups.    -   5. The chemical entity of clause 1, wherein R₁ is a pyrrolidine.    -   6. The chemical entity of clause 1, wherein R₂ is chosen from        carbonylalkyl and heterocarbonylalkyl groups.    -   7. The chemical entity of clause 1, wherein R₂ is chosen from        amides, reversed amides, and ureas.    -   8. The chemical entity of clause 1, wherein R₂ is an amide.    -   9. The chemical entity of clause 1, wherein R₃ is chosen from        aryl and heteroaryl rings.    -   10. The chemical entity of clause 1, wherein R₃ is chosen from        thiazole, indenyl, pyrazole, and phenyl rings.    -   11. The chemical entity of clause 1, wherein R₃ is chosen from        cyclic and heterocyclic rings.    -   12. The chemical entity of clause 1, wherein m is 0.    -   13. The chemical entity of clause 1, wherein R₄ is chosen from        cyclic and heterocyclic rings optionally substituted with 1 or 2        R.    -   14. The chemical entity of clause 1, wherein R₄ is chosen from        alkyl, heteroalkyl, and haloalkyl groups.    -   15. The chemical entity of clause 1, wherein R₄ is chosen from        aryl and heteroaryl rings optionally substituted with 1 or 2 R.    -   16. The chemical entity of clause 1 wherein R is chosen from        halogens.    -   17. The chemical entity of clause 1, chosen from the following        compounds:

Example No. Structure Chemical Name Compound 10-1

cis-4-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1-carboxamide Compound 10-2

trans-4-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1-carboxamide Compound 10-3

(1R,2R)-2-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compound 10-4

(1R,3S)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1-carboxamide Compound 10-5

(1S,3S)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1-carboxamide Compound 10-6

(1S,3R)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2- yl)cyclohexane-1-carboxamide Compound 10-7

(1R,2S)-2-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compound 10-8

(1S,2R)-2-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compund 10-9

(1S,2S)-2-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compound 1-1

trans-3-(cyanoamino)-N-[5- (oxan-4-yl)-1,3-thiazol-2- yl]cyclobutane-1-carboxamide Compound 10-10

(1S,3S)-3-(cyanoamino)-N- [5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide Compound 10-11

(1R,3R)-3-(cyanoamino)-N- [5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide Compound 11-1

trans-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclopropane-1-carboxamide Compound 11-2

cis-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclopropane-1-carboxamide Compound 2-1

3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)azetidine-1-carboxamide Compound 2-2

(3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)pyrrolidine-1-carboxamide Compound 2-3

(3R)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)pyrrolidine-1-carboxamide Compound 3-1

5-phenyl-N-[(trans)-3- (cyanoamino)cyclobutyl]-1,3-thiazole-2-carboxamide Compound 4-1

5-phenyl-N-[(cis)-3- (cyanoamino)cyclobutyl]- 1,3-thiazole-2-carboxamideCompound 12-1

(1R,3S)-3-(cyanoamino)-N- (5-phenyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide Compound 12-2

(1S,3S)-3-(cyanoamino)-N- (1-phenyl-1H-pyrazol-3- yl)cyclopentane-1-carboxamide Compound 12-3

(1S,3S)-3-(cyanoamino)-N- (5-cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1- carboxamide Compound 12-4

(1S,3S)-3-(cyanoamino)-N- (5-phenyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide Compound 5-1

cis-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-4- yl)cyclobutane-1-carboxamide Compound 5-2

cis-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-3- yl)cyclobutane-1-carboxamide Compound 5-3

cis-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- y)cyclobutane-1-carboxamide Compound 5-4

cis-3-(cyanoamino)-N-(5- phenyl-1,3-thiazol-2- yl)cyclobutane-1-carboxamide Compound 5-5

trans-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-4- yl)cyclobutane-1-carboxamide Compound 5-6

trans-3-(cyanoamino)-N-(1- phenyl-1H-pyrazol-3- yl)cyclobutane-1-carboxamide Compound 5-7

trans-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclobutane-1-carboxamide Compound 5-8

trans-3-(cyanoamino)-N-(5- phenyl-1,3-thiazol-2- yl)cyclobutane-1-carboxamide Compound 12-5

(1S,3S)-3-(cyanoamino)-N- (2,3-dihydro-1H-inden-5- yl)cyclopentane-1-carboxamide Compound 12-6

{[(1S,3S)-3-(4- phenylpiperazine-1- carbonyl)cyclopentyl]amino}carbonitrile Compound 12-7

(1S,3R)-N-(5-tert-butyl-1,3- thiazol-2-yl)-3- (cyanoamino)cyclopentane-1-carboxamide Compound 5-9

cis-3-(cyanoamino)-N-(2,3- dihydro-1H-inden-5- yl)cyclobutane-1-carboxamide Compound 5-10

cis-N-(5-tert-butyl-1,3- thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide Compound 5-11

{[cis-3-(4-phenylpiperazine- 1- carbonyl)cyclobutyl]amino} carbonitrileCompound 5-12

trans-3-(cyanoamino)-N- (2,3-dihydro-1H-inden-5- yl)cyclobutane-1-carboxamide Compound 5-13

trans-N-(5-tert-butyl-1,3- thiazol-2-yl)-3- (cyanoamino)cyclobutane-1-carboxamide Compound 5-14

trans-3-(cyanoamino)-N-[4- (morpholin-4- yl)phenyl]cyclobutane-1-carboxamide Compound 12-8

{[(3S)-1-[2-(2,3- dichlorophenyl)-1,3- thiazole-4-carbonyl]pyrrolidine-3- yl]amino}carbonitrile Compound 12-9

({1-[2-(2,4-dichlorophenyl)- 1,3-thiazole-4- carbonyl]piperidine-4-yl}amino)carbonitrile

-   -    and pharmaceutically acceptable salts, solvates, prodrugs,        stereoisomers, and tautomers thereof.    -   18. A composition comprising at least one chemical entity of any        one of clauses 1-17, and a pharmaceutically acceptable carrier.    -   19. A method of inhibiting USP30 in vitro comprising        administering to a Ubiquitin-Rhodamine 110 assay for USP30        activity an effective amount of at least one chemical entity of        any one of clauses 1-17.    -   20. A method for treating at least one disease, disorder, or        condition associated with mitochondrial dysfunction comprising        administering to a patient in need thereof an effective amount        of at least one chemical entity of any one of clauses 1-17.    -   21. The method of clause 20, wherein the at least one disease,        disorder, or condition is chosen from neurodegenerative        diseases, motor neuron diseases, metabolic disorders,        cardio-vascular diseases, psychiatric diseases, osteoarthritis,        and cancer.    -   22. The method of clause 21, wherein the neurodegenerative        disease is chosen from Alzheimer's disease, Parkinson's disease,        dementia, Prion disease, corticobasal degeneration, Posterior        Cortical Atrophy, Primary Progressive Aphasia, Progressive        Supranuclear Palsy, Pick's disease, Chronic Traumatic        Encephelopathy, Traumatic Brain Injury, peripheral neuropathy,        and multiple sclerosis.    -   23. The method of clause 21, wherein the motor neuron disease is        chosen from Amyltrophic Lateral Sclerosis (ALS), Huntington's        disease, Spinocerebellar Ataxia, Ataxia, and Spinal Muscular        Atrophy.    -   24. The method of clause 21 wherein the metabolic disorder is        chosen from diabetes, mitochondrial encephalomyopathy,        Stroke-Like Episodes (MELAS), mitochondrial myopathy,        encephalopathy, lactic acidosis, Leber's hereditary optic        neuropathy (LHON), neuropathy, ataxia, retinitis        pigmentosa-maternally inherited Leigh syndrome (NARP-MILS),        Danon disease, diabetic nephropathy, retinitis        pigmentosa-maternally inherited Leigh syndrome (NARP-MILS),        multiple sulfatase deficiency (MSD), mucolipidosis II (ML II),        mucolipidosis III (ML III), mucolipidosis IV (ML IV),        GM1-gangliosidosis (GM1), neuronal ceroid-lipofuscinoses (NCLl),        Alpers disease, Barth syndrome, Beta-oxidation defects,        camitine-acyl-camitine deficiency, camitine deficiency, creatine        deficiency syndrome, co-enzyme Q 10 deficiency, complex I        deficiency, complex II deficiency, CPT I deficiency, CPT II        deficiency, glutaric aciduria type II, Keams-Sayre syndrome,        lactic acidosis, long-chain acyl-CoA dehydrogenase deficiency        (LCHAD), Leigh disease complex III deficiency, complex IV        deficiency, complex V deficiency, COX deficiency, chronic        progressive external syndrome, lethal infantile cardiomyopathy        (LIC), Luft disease, glutaric aciduria type II, medium-chain        acyl-CoA dehydrogenase deficiency (MCAD), myoclonic epilepsy and        ragged-red fiber (MERRF) syndrome, mitochondrial cytopathy,        mitochondrial recessive ataxia syndrome, mitochondrial DNA        depletion syndrome, myoneurogastrointestinal disorder and        encephalopathy, Pearson syndrome, pyruvate dehydrogenase        deficiency, pyruvate carboxylase deficiency, POLG        ophthalmoplegia syndrome mutations, medium/short-chain        3-hydroxyacyl-CoA dehydrogenase (M/SCHAD) deficiency, and very        long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.    -   25. The method of clause 21 wherein the cardiovascular disorder        is chosen from transthyretin amyloidosis, heart failure,        ischemic heart disease leading to cardiac infarction, and        cardiac amyloidosis.    -   26. The method of clause 21 wherein the psychiatric disease is        chosen from schizophrenia, depression, and general anxiety        disorder.    -   27. The method of clause 21, wherein the cancer is chosen from        bladder cancer, breast cancer, cervical cancer, colorectal        cancer, esophageal cancer, gastric cancer, head and neck cancer,        hematologic cancer, lung cancer, liver cancer, lymphoma,        neurological cancer, ovarian, pancreatic cancer, prostate        cancer, renal cancer, sarcoma, skin cancer, thyroid cancer, and        uterine cancer.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R isindependently chosen from hydrogen, OH, CN, (C₁-C₆) alkyl, (C₁-C₆)alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₆)cycloalkyl, and (C₃-C₆) heterocycloalkyl; n is 0, 1, or 2; wherein, if nis 2, the R groups can combine to form a fused ring system with R₁; R₁is a 3-6 membered carbocyclic or heterocyclic ring; R₂ is chosen fromamides, reverse amides, and ureas; X is independently chosen fromhydrogen, alkyl, and heteroalkyl, wherein the alkyl and heteroalkyl canoptionally cyclize with R, R₁, or R₃ or with another X group whenmultiple X groups are present; R₃ is chosen from hydrogen, halogen,alkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, haloalkoxy,carbonylalkyl, carbonylheteroalkyl, carbocyclic, heterocyclic, aryl, andheteroaryl, wherein any rings are optionally substituted with 1 or 2 R;R₄ is independently chosen from alkyl, heteroalkyl, haloalkyl, alkoxy,cycloalkoxy, heteroalkoxy, haloalkoxy, carboxyalkyl, heterocarboxyalkyl,carbocyclic, heterocyclic, aryl and heteroaryl, wherein any rings areoptionally substituted with 1 or 2 Y groups; Y is independently chosenfrom hydrogen, OH, CN, N(X)₂, (C₁-C₆) alkyl, (C₁-C₆) heteroalkyl,(C₁-C₆) alkoxy, (C₁-C₆) haloalkyl, (C₁-C₆) haloalkoxy, halogen, (C₃-C₆)cycloalkyl, (C₃-C₆) heterocycloalkyl, (C₅-C₈) aryl, and (C₄-C₈)heteroaryl; and m is 0, 1, or
 2. 2. The compound of claim 1, wherein R₁is a 4-membered carbocyclic or heterocyclic ring.
 3. (canceled)
 4. Thecompound of claim 1, wherein R₁ is chosen from cyclobutane andcyclopentane. 5-6. (canceled)
 7. The compound of claim 1, wherein R₂ isan amide.
 8. The compound of claim 1, wherein R₃ is chosen from aryl andheteroaryl rings.
 9. The compound of claim 1, wherein R₃ is chosen fromthiazole, indenyl, pyrazole, and phenyl rings.
 10. The compound of claim1, wherein R₃ is chosen from carbocyclic and heterocyclic rings.
 11. Thecompound of claim 1, wherein m is
 0. 12. The compound of claim 1,wherein R₄ is chosen from carbocyclic and heterocyclic rings optionallysubstituted with 1 or 2 Y.
 13. The compound of claim 1, wherein R₄ ischosen from alkyl, heteroalkyl, and haloalkyl.
 14. The compound of claim1, wherein R₄ is chosen from aryl and heteroaryl rings optionallysubstituted with 1 or 2 Y.
 15. The compound of claim 1, wherein R ishalogen.
 16. (canceled)
 17. A pharmaceutical composition comprising thecompound of claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 18. A compound selected from:Compound 10-1

cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide; Compound 10-2

trans-4-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclohexane-1-carboxamide; Compound 10-3

(1R,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 10-4

(1R,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide; Compound 10-5

(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide; Compound 10-6

(1S,3R)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane-1-carboxamide; Compound 10-7

(1R,2S)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 10-8

(1S,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 10-9

(1S,2S)-2-(cyanoamino)-N-(5- cyclohexy1-1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 10-10

(1S,3S)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide; Compound 10-11

(1R,3R)-3-(cyanoamino)-N-[5-(oxan-4-yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide; Compound 11-1

trans-2-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclopropane-1-carboxamide; Compound 11-2

cis-2-(cyanoamino)-N-(5-cyclohexy1-1,3- thiazol-2-yl)cyclopropane-1-carboxamide; Compound 2-2

(3S)-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)pyrrolidine-1-carboxamide; Compound 2-3

(3R)-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)pyrrolidine-1-carboxamide; Compound 12-1

(1R,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 12-2

(1S,3S)-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-3-yl)cyclopentane-1-carboxamide; Compound 12-3

(1S,3S)-3-(cyanoamino)-N-(5- cyclohexy1-1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 12-4

(1S,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1-carboxamide; Compound 12-5

(1S,3S)-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclopentane-1-carboxamide; Compound 12-6

{[(1S,3S)-3-(4-phenylpiperazine-1-carbonyl)cyclopentyl]amino}carbonitrile; Compound 12-7

(1S,3R)-N-(5-tert-buty1-1,3-thiazol-2-y1)- 3-(cyanoamino)cyclopentane-1-carboxamide; Compound 12-8

{[(3S)-1-[2-(2,3-dichlorophenyl)-1,3- thiazole-4-carbonyl]pyrrolidin-3-yl]amino}carbonitrile; and Compound 12-9

({1-[2-(2,4-dichlorophenyl)-1,3-thiazole- 4-carbonyl]piperidin-4-yl}amino)carbonitrile

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising the compound of claim 18 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. 20.The compound of claim 1, wherein R₁ is chosen from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and pyrrolidine.
 21. Thecompound of claim 20, wherein R₃ is chosen from aryl and heteroarylrings.
 22. The compound of claim 21, wherein R₄ is chosen fromcarbocyclic and heterocyclic rings optionally substituted with 1 or 2 Y.23. The compound of claim 8, wherein R₄ is chosen from carbocyclic andheterocyclic rings optionally substituted with 1 or 2 Y.